rs143456784

Positions:

chr7-117504324-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000003084.11(CFTR):c.125C>T(p.Ser42Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,608,896 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 6.12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.125C>T	p.Ser42Phe	missense_variant	2/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.125C>T	p.Ser42Phe	missense_variant	2/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

250878

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

195

AN:

1456766

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

725138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000170

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2022	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 42 of the CFTR protein (p.Ser42Phe). This variant is present in population databases (rs143456784, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autoimmune pancreatitis, cystic fibrosis, and/or or pancreatic cancer (PMID: 15084222, 19885835, 23276700, 25869325). ClinVar contains an entry for this variant (Variation ID: 35819). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2022	The p.S42F variant (also known as c.125C>T), located in coding exon 2 of the CFTR gene, results from a C to T substitution at nucleotide position 125. The serine at codon 42 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was first reported in an individual with cystic fibrosis; however, clinical information and a second alteration were not described (Férec C et al. Mol. Cell. Probes, 1995 Apr;9:135-7). This variant was also identified in a healthy individual undergoing carrier screening in conjunction with a second CFTR alteration (Picci L et al. J. Cyst. Fibros., 2010 Jan;9:29-35). In addition, this variant was detected in four individuals with autoimmune pancreatitis; however, PRSS1 and SPINK1 genotyping results were not provided (Chang MC et al. J. Cyst. Fibros., 2015 Sep;14:661-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2022	BP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	The CFTR c.125C>T; p.Ser42Phe variant (rs143456784) is reported in individuals with cystic fibrosis or CFTR-related disorders (Chang 2015, D'Apice 2004, Ferec 1995, Lucarelli 2015, Picci 2010, Soltysova 2018); however, in most of these individuals a second pathogenic variant was not identified and limited clinical information was provided. This variant has also been identified in cis with other pathogenic CFTR variants (Krenkova 2013, Padoan 2006). This variant is reported in ClinVar (Variation ID: 35819). It is observed in the general population with an overall allele frequency of 0.01% (30/250878 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.714). Due to limited and conflicting information, the clinical significance of this variant is uncertain at this time. References: Chang MC et al. Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. J Cyst Fibros. 2015 Sep;14(5):661-7. PMID: 25869325. D'Apice MR et al. Molecular analysis using DHPLC of cystic fibrosis: increase of the mutation detection rate among the affected population in Central Italy. BMC Med Genet. 2004 Apr 14;5:8. PMID: 15084222. Ferec C et al. Identification of six novel CFTR mutations in a sample of Italian cystic fibrosis patients. Mol Cell Probes. 1995 Apr;9(2):135-7. PMID: 7541510. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Lucarelli M et al. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. Mol Med. 2015 Apr 21;21(1):257-75. PMID: 25910067. Padoan R et al. Identification of the 5T-12TG allele of the cystic fibrosis transmembrane conductance regulator gene in hypertrypsinaemic newborns. Acta Paediatr. 2006 Jul;95(7):871-3. PMID: 16801189. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010 Jan;9(1):29-35. PMID: 19897426. Soltysova A et al. Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. Clin Respir J. 2018 Mar;12(3):1197-1206. PMID: 28544683. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	Observed in individuals with cystic fibrosis without a second variant reported (Ferec 1995, D'Apice 2004, Lucarelli 2015, Soltysova 2018); Observed with a pathogenic variant on the same allele (in cis) in published literature (Krenkova 2013); Observed with a pathogenic variant on the opposite allele (in trans) in a patient without cystic fibrosis in published literature (McWilliams 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12007216, 19885835, 15084222, 15536480, 16251901, 7541510, 25869325, 25735457, 25087612, 25910067, 16126774, 16801189, 19652440, 19897426, 23276700, 28544683) -

CFTR-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 21, 2023	The CFTR c.125C>T variant is predicted to result in the amino acid substitution p.Ser42Phe. This variant has been documented in cohorts of patients with infertility (Chamayou et al. 2020. Pub Med ID: 32357917; Oud et al. 2017. PubMed ID: 28801929), pancreatitis (Chang et al. 2015. PubMed ID: 25869325), cystic fibrosis (Soltysova et al. 2017. PubMed ID: 28544683; Ferec et al. 1995. PubMed ID: 7541510), and abnormal sweat chloride testing (Padoan et al. 2006. PubMed ID: 16801189). However, this variant has also been documented both in cis with a CFTR nonsense variant and in trans with the p.Phe508del variants in unaffected inviduals (Křenková et al. 2013. PubMed ID: 23276700; McWilliams et al. 2010. PubMed ID: 19885835). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including a homozygous individual (http://gnomad.broadinstitute.org/variant/7-117144378-C-T). This variant has been interpreted by multiple submitters in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/35819). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 04, 2024

Variant summary: CFTR c.125C>T (p.Ser42Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 279934 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00011 vs 0.013), allowing no conclusion about variant significance. c.125C>T has been reported in the literature in the heterozygous, compound heterozygous, and presumed compound heterozygous states in multiple individuals affected with infertility (example, Oud_2017, Chamayou_2020, Smits_2019), CBAVD (example, Claustres_2017), autoimmune pancreatitis (example, Chang_2015), pancreatic adenocarcinoma (example, McWilliams_2010), elevated immunoreactive trypsinogen (IRT, example Castellani_2017) and (suspected) Cystic Fibrosis (example Ferec_1995, DApice_2004, Picci_2010, Guissart_2015, Padoan_2006, Lucarelli_2015, Soltysova_2015). However, in most of these cases a non-informative genotype (no pathogenic variant in trans) was reported; these data therefore do not allow clear conclusions about variant significance. In addition, in at least 2 of these reported cases a co-occurrence with other pathogenic variants in cis have been reported (CFTR c.223C>T (p.Arg75X) in Krenkova_2013, and CFTR 5T_TG12 in Padoan_2006 and/or Colombo_2007), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12007216, 32357917, 25869325, 28603918, 24813944, 15084222, 7541510, 25274949, 23276700, 25910067, 19885835, 15536480, 16126774, 28801929, 16801189, 19897426, 16251901, 25735457, 28544683, 25087612, 26755536, 17407489, 31672438). ClinVar contains an entry for this variant (Variation ID: 35819). 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

Feb 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.5

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.2

D;.;.;D;.

REVEL

Pathogenic

0.71

Sift

Benign

0.052

T;.;.;T;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.46

P;.;.;.;.

Vest4

0.86

MVP

0.99

MPC

0.0053

ClinPred

0.28

GERP RS

5.6

Varity_R

0.22

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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