rs149279509

Positions:

chr7-117610571-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP3BP4

The NM_000492.4(CFTR):c.3041A>G(p.Tyr1014Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:17

Conservation

PhyloP100: 8.89

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

ENSG00000083622 (HGNC:):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain ABC transmembrane type-1 2 (size 296) in uniprot entity CFTR_HUMAN there are 53 pathogenic changes around while only 8 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.26682281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3041A>G	p.Tyr1014Cys	missense_variant	19/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3041A>G	p.Tyr1014Cys	missense_variant	19/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000279

AC:

AN:

251138

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461222

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000649

Gnomad4 ASJ exome

AF:

0.00325

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000657

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000197

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1014 of the CFTR protein (p.Tyr1014Cys). This variant is present in population databases (rs149279509, gnomAD 0.4%). This missense change has been observed in individual(s) with known or suspected with cystic fibrosis and idiopathic chronic pancreatitis, recurrent acute pancreatitis, pancreatic cancer, gastric cancer, and congenital bilateral absence of the vas deferens (PMID: 11466205, 17331079, 17663888, 18687795, 23951356, 25383785, 26182300, 28546993). ClinVar contains an entry for this variant (Variation ID: 53638). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	research	CFTR2	Oct 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2023	The p.Y1014C variant (also known as c.3041A>G), located in coding exon 19 of the CFTR gene, results from an A to G substitution at nucleotide position 3041. The tyrosine at codon 1014 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first described in the heterozygous state in two males presenting with congenital bilateral absence of the vas deferens (CBAVD) (Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83; Larriba S et al. Biol. Reprod., 2001 Aug;65:394-400). This variant was also reported in two individuals with abnormal nasal potential differences and acute recurrent pancreatitis. One of these individuals had a sweat chloride level of 100 mEq/L and also carried p.W1282*, while the other individual had a sweat chloride level of 54 mEq/L and carried p.R117H; the phase was not determined in either individual (Werlin S et al. J. Pediatr. Gastroenterol. Nutr., 2015 May;60:675-9). In another study, this variant was found in an individual with bronchiectasis and a negative sweat chloride level in conjunction with the 5T allele; however, the phase was not determined (Casals T et al. Clin. Genet., 2004 Jun;65:490-5). This variant was also detected in three individuals with chronic pancreatitis, both with and without another CFTR alteration (de Cid R et al. Pancreas, 2010 Mar;39:209-15). In CFBE cells, chloride conductance for this variant was 74% of wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 23, 2020	CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information. -

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 09, 2023	The frequency of this variant in the general population, 0.0038 (39/10364 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been identified alone or with another pathogenic CF variant in individuals with known or suspected cystic fibrosis or with CFTR-related disorders (PMIDs: 11466205 (2001), 15151509 (2004), 17331079 (2007), 23951356 (2013), 25383785 (2015), 27449771 (2016), 28546993 (2017), 30888834 (2019), and 31665830 (2020)). Functional studies indicated that this variant shows a moderate decrease in CFTR protein function (PMIDs: 29805046 (2018), 30888834 (2019), and 34996830 (2022)). Taking into account the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2024	Published functional studies are inconclusive: does not significantly affect CFTR function (PMID: 29805046); Observed multiple times with a pathogenic variant in individuals with cystic fibrosis and atypical cystic fibrosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 28546993); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of unknown significance in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 26847993, 11466205, 27449771, 25087612, 23951356, 10875853, 29589582, 27022295, 25383785, 25203624, 19812525, 17331079, 15151509, 18687795, 23687349, 32003480, 32734384, 34996830, 31036917, 36207272, 31665830, 33922413, 35652053, 34797250, 32773111, 35913788, 34842611, 29805046, 28546993, 38271453, 38388235, 34405919, 36372909) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CFTR p.Tyr1014Cys variant was identified in the literature in cases of Cystic Fibrosis (CF) or congenital absence of the vas deferens (CAVD) as well as in healthy controls. The variant was identified in the heterozygous state in 3/176 Israeli CF patients lacking a known molecular diagnosis and in 2/977 Spanish families with CF (freq=0.001) (Behar_2017_PMID:28546993; Alonso_2007_PMID:17331079). The variant was also found in 1/134 men (freq=0.004) with CAVD (Casals_2000_PMID:10875853). A study of 512 unaffected Portuguese children reported the Y1014C variant in the heterozygous state in 2 children (Grangeia_2018_PMID:29589582). Functional studies of multiple known or suggested CF variants showed that the Y1014C variant retained ~74% of wildtype function, compared to less than 1% of wildtype function from the well-known deltaF508 CF mutation; this does not suggest a strong functional effect of the Y1014C variant (Raraigh_2018_PMID:29805046). The variant was also identified in dbSNP (ID: rs149279509), LOVD 3.0 and ClinVar (classified as a VUS by EGL Genetic Diagnostics, Quest Diagnostics and Integrated Genetics/Laboratory Corporation of America) but was not found in Cosmic. The variant was identified in control databases in 73 of 282520 chromosomes at a frequency of 0.000258 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 39 of 10364 chromosomes (freq: 0.003763), Other in 4 of 7198 chromosomes (freq: 0.000556), Latino in 17 of 35350 chromosomes (freq: 0.000481) and European (non-Finnish) in 13 of 129000 chromosomes (freq: 0.000101); it was not observed in the African, East Asian, European (Finnish), and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Tyr1014 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2019	The CFTR c.3041A>G; p.Tyr1014Cys variant (rs149279509) is reported in the literature in multiple individuals affected with cystic fibrosis (Alonso 2007, Behar 2017, Sanchez 2016) or CFTR-related disorders (Audrezet 2008, Casals 2000, Casals 2004, de Cid 2010, Larriba 2001, Masson 2013, Trujillano 2013), in some of whom a second pathogenic CFTR variant was identified. This variant is reported in ClinVar (Variation ID: 53638), and is found in the Ashkenazi Jewish population with an allele frequency of 0.38% (39/10364 alleles) in the Genome Aggregation Database. The tyrosine at codon 1014 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a moderate decrease in protein function (Raraigh 2018). However, based on available information, the clinical significance of the p.Tyr1014Cys variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007 Mar;71(Pt 2):194-201. Audrezet MP et al. Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. J Mol Diagn. 2008 Sep;10(5):424-34. Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000 Jul;15(7):1476-83. Casals T et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations? Clin Genet. 2004 Jun;65(6):490-5. de Cid R et al. Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas. 2010 Mar;39(2):209-15. Larriba S et al. Adenosine triphosphate-binding cassette superfamily transporter gene expression in severe male infertility. Biol Reprod. 2001 Aug;65(2):394-400. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013 Jul;50(7):455-62. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Sanchez K et al. Analysis of the CFTR gene in Venezuelan cystic fibrosis patients, identification of six novel cystic fibrosis-causing genetic variants. Appl Clin Genet. 2016 Mar 8;9:33-8. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2023	PP3 -

CFTR-related disorder

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2024	The CFTR c.3041A>G variant is predicted to result in the amino acid substitution p.Tyr1014Cys. This variant has been reported in multiple individuals with cystic fibrosis and CFTR-related phenotypes including congenital absence of the vas deferens, pancreatitis, and bronchiectasis (Casals et al. 2000. PubMed ID: 10875853; Larriba et al. 2001. PubMed ID: 11466205; Casals et al. 2004. PubMed ID: 15151509; de Cid et al. 2010. PubMed ID: 19812525; Werlin et al. 2015. PubMed ID: 25383785; Sánchez et al. 2016. PubMed ID: 27022295; Behar et al. 2017. PubMed ID: 28546993; Zeiger et al. 2020. PubMed ID: 31665830). In vitro functional studies indicate that the p.Tyr1014Cys variant retains approximately 74-75% of CFTR function compared to control (Raraigh et al 2018. PubMed ID: 29805046; McCague et al. 2019. PubMed ID: 30888834). This variant is reported in 0.38% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In the ClinVar database, multiple clinical laboratories interpret this variant as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/53638/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 22, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 15, 2024

Variant summary: CFTR c.3041A>G (p.Tyr1014Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251138 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00028 vs 0.013), allowing no conclusion about variant significance. c.3041A>G has been reported in the literature in individuals affected with Non-Classic Cystic Fibrosis and CFTR-related phenotypes, including CBAVD, pancreatitis, bronchiectasis, and CF (examples: Casals_2000, Casals_2004, Alonso_2007, Fuster_2007, Audrezet_2008, Werlin_2014, Sanchez_2016, Behar_2017, Zeiger_2019, Saferali_2022). In the majority of these cases, a second mutation was not specified, however at least four patients with a CF phenotype have been reported to carry the variant in compound heterozygosity with another known pathogenic variant (e.g. Fuster 2007, Behar 2017). In addition, the variant has been reported as compound heterozygous genotype in two patients with recurrent acute pancreatitis who carried another pathogenic CFTR variant (though the phase was not tested). These patients were assessed to have abnormal nasal potential differences and elevated sweat chloride levels, indicating a loss of CFTR function (e.g. Werlin 2014). Collectively, these data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. In these studies, cells expressing the variant with or without a second pathogenic mutation had approximately 50-75% wild-type CFTR function (e.g. Raraigh_2018, McCague_2019, Bihler_2024). Disease association was indeterminate based upon these findings. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 18687795, 31036917, 28546993, 25203624, 15151509, 10875853, 17663888, 29589582, 36969284, 36372909, 26182300, 11466205, 26847993, 25880441, 23951356, 30888834, 29805046, 34996830, 27022295, 25087612, 29669919, 23687349, 25383785, 27449771, 31665830, 19812525, 38388235). ClinVar contains an entry for this variant (Variation ID: 53638). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

2.9

M;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.3

D;.;.;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.011

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.95

MVP

0.99

MPC

0.015

ClinPred

0.26

GERP RS

6.2

Varity_R

0.84

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over