rs150691494

chr7-117540132-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000492.4(CFTR):c.902A>G(p.Tyr301Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,613,246 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y301H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 5.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a transmembrane_region Helical; Name=5 (size 20) in uniprot entity CFTR_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13123178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.902A>G	p.Tyr301Cys	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.902A>G	p.Tyr301Cys	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000291 AC: 73 AN: 250950 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461060 Hom.: 0 Cov.: 30 AF XY: 0.000219 AC XY: 159 AN XY: 726886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000432 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2023	The p.Y301C variant (also known as c.902A>G), located in coding exon 8 of the CFTR gene, results from an A to G substitution at nucleotide position 902. The tyrosine at codon 301 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in two newborns with an elevated immunoreactive trypsinogen (IRT) and normal sweat chloride levels, who were also heterozygous for p.F508del (Castellani C et al. Am. J. Hum. Genet., 1999 Jan;64:303-4; Ooi CY et al. Pediatrics, 2015 Jun;135:e1377-85). This variant was detected as heterozygous in a newborn with cystic fibrosis-related metabolic syndrome and in 1/177 CF and CFTR-related patients, but a second CFTR alteration was not detected in these patients (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403; Baaran AE et al. Turk J Med Sci, 2019 Dec;49:1655-1661). In another study, this variant was identified in an individual with cystic fibrosis; however, complete genotype and phenotype information was not provided (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This alteration was also identified in an individual with asthma and an individual with lung cancer (Tzetis M et al. Hum. Genet., 2001 Mar;108:216-21; Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22). This variant was also detected in 1/1279 Sicilian infertile patients who underwent CFTR screening (Chamayou S et al. BMC Med Genet, 2020 May;21:89). This amino acid position is well 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	Invitae	Oct 23, 2022	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 301 of the CFTR protein (p.Tyr301Cys). This variant is present in population databases (rs150691494, gnomAD 0.5%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9921909, 11303517, 11354633, 23276700, 28040058). ClinVar contains an entry for this variant (Variation ID: 198738). 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. -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2017	The Y301C variant in the CFTR gene has been reported previously in individuals with an additional variant in CFTR who screened positive for cystic fibrosis on newborn screening; however, these individuals had inconclusive diagnosis with normal sweat chloride levels at followup (Castellani et al., 1999; Ooi et al., 2015). The Y301C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y301C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R297W, A299T) have been reported in the Human Gene Mutation Database in association with CFTR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y301C as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2023	The CFTR c.902A>G; p.Tyr301Cys variant (rs150691494) is reported in the literature in individuals with cystic fibrosis or related symptoms (El-Seedy 2016, Krenkova 2013) and in several newborns with hypertrypsinemia or a positive newborn screen but also normal sweat chloride (Castellani 1999, Ooi 2015, Scotet 2001). This variant is also reported in ClinVar (Variation ID: 198738), and is found in the Ashkenazi Jewish population with an overall allele frequency of 0.42% (44/10364 alleles) in the Genome Aggregation Database. The tyrosine at codon 301 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.860). However, given the lack of clinical and functional data, the significance of the p.Tyr301Cys variant is uncertain at this time. References: El-Seedy A et al. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations in North Egyptian population: implications for the genetic diagnosis in Egypt. Cell Mol Biol (Noisy-le-grand). 2016 Nov 30;62(13):21-28. PMID: 28040058. Castellani C et al. Cystic fibrosis mutations in heterozygous newborns with hypertrypsinemia and low sweat chloride. Am J Hum Genet. 1999 Jan;64(1):303-4. PMID: 9915972. 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. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. PMID: 25963003. Scotet V et al. Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis. Clin Genet. 2001 Jan;59(1):42-7. PMID: 11168024. -

CFTR-related disorders Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 30, 2017	- -
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

Oct 02, 2023

Variant summary: CFTR c.902A>G (p.Tyr301Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251692 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00029 vs 0.013), allowing no conclusion about variant significance. c.902A>G has been reported in the literature in sequencing/genotyping studies, as examples, 1. with p.F508del in a neonate with raised immunoreactive trypsinogen concentration (IRT) and low sweat chloride (18 mEq/liter), 2. in a patient in low sweat chloride (<30 mmol/L) and an inconclusive diagnosis of CF (Castellani_1999, Ooi_2015), 3. as a non-informative genotype in patients with asthama (Tzetis_2001), lung cancer (Bombieri_1998), infertility (Chamayou_2020), unaffected carriers (Scotet_2001), settings of diagnostic CF genotyping (Wei_2006, Krenkova_2012, Trujillano_2015, El-Seedy_2016), 4. with other CFTR variants in patients/newborns lacking sufficient clinical evidence (Schwartz_2009, Poulou_2014, Olsowiec-Chlebna_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis or its associated phenotypes. 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: 11354633, 9921909, 11168024, 19324992, 11303517, 9915972, 23276700, 25963003, 24784896, 28040058, 26436105, 16617247, 32357917, 33836782). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. 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 18, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	D;.;.;D;.
REVEL	Pathogenic	0.86
Sift	Benign	0.061	T;.;.;T;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.95
MVP		0.99
MPC		0.0052
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.38
gMVP		0.91

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

Other links and lift over

dbSNP: rs150691494; hg19: chr7-117180186;