chr7-117610625-A-G

Position:

chr7-117610625-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000003084.11(CFTR):c.3095A>G(p.Tyr1032Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:1

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain ABC transmembrane type-1 2 (size 296) in uniprot entity CFTR_HUMAN there are 146 pathogenic changes around while only 15 benign (91%) in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 7-117610625-A-G is Pathogenic according to our data. Variant chr7-117610625-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117610625-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3095A>G	p.Tyr1032Cys	missense_variant	19/27	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.3095A>G	p.Tyr1032Cys	missense_variant	19/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+5604T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250986

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461380

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000483

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:5Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 17, 2023	The p.Y1032C variant (also known as c.3095A>G), located in coding exon 19 of the CFTR gene, results from an A to G substitution at nucleotide position 3095. The tyrosine at codon 1032 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was described in 2 individuals in conjunction with p.F508del (phase unknown); one individual had a positive newborn screen and indeterminate sweat chloride levels while the other had congenital bilateral absence of the vas deferens (CBAVD) and recurrent bronchitis (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Ren CL et al. Pediatr. Pulmonol., 2011 Nov;46:1079-84). In a Caucasian female who presented with a positive newborn screen, borderline sweat tests, and pancreatic sufficiency who went on to develop acute pancreatitis, this variant was in trans with p.F508del and p.R1438W (Leonardi S et al. J Med Case Rep, 2013 Jul;7:188). In CFBE cells, this variant showed reduced CFTR function compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3(14):pii 121159). The p.Y1032C alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;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 the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1032 of the CFTR protein (p.Tyr1032Cys). This variant is present in population databases (rs144055758, gnomAD 0.004%). This missense change has been observed in individuals with congenital absence of the vas deferens or cystic fibrosis (PMID: 9272157, 17329263, 19406970, 21520337, 23883480). ClinVar contains an entry for this variant (Variation ID: 35861). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2020	Variant summary: CFTR c.3095A>G (p.Tyr1032Cys) 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 1.6e-05 in 251624 control chromosomes. c.3095A>G has been reported in the literature and in multiple databases in compound heterozygous individuals with varying clinical consequences, ranging from Congenital Bilateral Absence of the Vas Deferens (CBAVD) to Cystic Fibrosis (usually with pancreatic sufficiency). There are 16 patients listed with this variant in the CFTR2 database, 27% of which are reported as pancreatic insufficient. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the variant results in 10%-<30% of normal CFTR activity (e.g. Raraigh_2018, Han_2018, McCague_2019). Five other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 06, 2018	The CFTR c.3095A>G (p.Tyr1032Cys) missense variant has been reported in four probands in seven different studies (DÃ¶rk et al. 1997; Corbetta et al. 2002; Padoan et al. 2006; Ratbi et al. 2007; Seia et al. 2009; Ren et al. 2011; Leonardi et al. 2013). The p.Tyr1032Cys variant was commonly reported in combination with the well-described severe pathogenic variant, p.Phe508del. However, only two of the seven probands had a clearly positive chloride sweat test and would be considered to have classic CF (DÃ¶rk et al. 1997; Seia et al. 2009). The p.Tyr1032Cys variant is associated with a mild phenotype (Leonardi et al. 2013). The p.Tyr1032Cys variant presented with various atypical CF phenotypes - persistent hypertrypsinogenaemia and a borderline chloride sweat test, acute pancreatitis at age six with a borderline chloride sweat test, and congenital bilateral absence of the vas deferens (CBAVD) and recurrent bronchitis (DÃ¶rk et al. 1997, Padoan et al. 2006, Ratbi et al. 2007; Seia et al. 2009; Ren et al. 2011; Leonardi et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Tyr1032Cys variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, flagged submission	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 19, 2021	- -

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 18, 2018	The CFTR c.3095A>G; p.Tyr1032Cys variant (rs144055758) is reported in individuals with atypical cystic fibrosis (i.e. monosymptomatic disease) when in combination with a severe pathogenic variant (Dork 1997, Leonardi 2013, Ratbi 2007, Ren 2011). This variant has varying clinical consequences and is commonly associated with pancreatic sufficiency (CFTR2 database). It is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 35861), and is found in the general population at a low overall allele frequency of 0.002% (4/245758 alleles) in the Genome Aggregation Database. The tyrosine at codon 1032 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered pathogenic and likely to be a mild pathogenic variant. REFERENCES CFTR2 database: https://www.cftr2.org Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. Leonardi S et al. Early acute pancreatitis in a child with compound heterozygosis F508/R1438W/Y1032C cystic fibrosis: a case report. J Med Case Rep. 2013 Jul 24;7:188. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91 Ren CL et al. Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome. Pediatr Pulmonol. 2011 Nov;46(11):1079-84. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect (Han 2018, Raraigh 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 12133923, 28603918, 9272157, 27171515, 30046002, 11883825, 16801189, 19318035, 30888834, 21538969, 17407489, 21520337, 29805046, 17329263, 23883480, 35523714, 35451201, Tosco[letter]2022, 35913788) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 20, 2022	PM2, PM3, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2022	In the published literature, the variant has been reported in individuals affected with Cystic Fibrosis or Cystic Fibrosis related disorders (CFRD) in the published literature (PMID: 27171515 (2016), 26277102 (2015), 25910067 (2015), 21538969 (2011), 21520337 (2011), 19406970 (2009)). In addition, this variant has been shown to affect CFTR chloride conductance function (PMID: 30046002 (2018), 29805046 (2018)). Based on the available information, the variant is classified as likely pathogenic. -

CFTR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 19, 2021	- -

Obstructive azoospermia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Reproductive Genetics, University of Münster

Mar 16, 2022

- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.7

H;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.5

D;.;.;D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MVP

1.0

MPC

0.012

ClinPred

0.99

GERP RS

6.2

Varity_R

0.93

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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