rs397508567

Positions:

chr7-117614703-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000492.4(CFTR):c.3458T>A(p.Val1153Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000342 in 1,608,492 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5O:1

Conservation

PhyloP100: 6.10

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 7-117614703-T-A is Pathogenic according to our data. Variant chr7-117614703-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53747.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr7-117614703-T-A 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.3458T>A	p.Val1153Glu	missense_variant	21/27	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.3458T>A	p.Val1153Glu	missense_variant	21/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250860

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135580

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:

0.0000618

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000350

AC:

AN:

1456396

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

724822

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000443

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2021	This sequence change replaces valine with glutamic acid at codon 1153 of the CFTR protein (p.Val1153Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is present in population databases (rs397508567, ExAC 0.008%). This missense change has been observed in individuals with congenital absence of the vas deferens and/or suspected cystic fibrosis (PMID: 9272157, 17329263, 26900683, 29805046). ClinVar contains an entry for this variant (Variation ID: 53747). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). 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, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2023	The p.V1153E variant (also known as c.3458T>A), located in coding exon 21 of the CFTR gene, results from a T to A substitution at nucleotide position 3458. The valine at codon 1153 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been detected as compound heterozygous with other CFTR variants in individuals with congenital bilateral absence of the vas deferens (CBAVD), as well as asymptomatic individuals (Dörk T et al. Hum Genet, 1997 Sep;100:365-77; Steiner B et al. Hum Mutat, 2011 Aug;32:912-20; Claustres M et al. Hum Mutat, 2017 10;38:1297-1315; Pagin A et al. PLoS One, 2016 Feb;11:e0149426). This variant has also been detected in the heterozygous state in individuals with CBAVD or allergic bronchopulmonary aspergillosis (ABPA) who did not have a second variant identified (Ratbi I et al. Hum Reprod, 2007 May;22:1285-91; Lebecque P et al. Thorax, 2011 Jun;66:540-1). Functional analysis of this variant in CFBE cells demonstrated 18% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). 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, this variant is unlikely to be causative of classic cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 17, 2018	The CFTR c.3458T>A (p.Val1153Glu) missense variant has been reported in four individuals, including in a compound heterozygous state with an intron variant in one individual with congenital bilateral absence of the vas deference (CBAVD), and in a heterozygous state without a second identified variant in one individual with cystic fibrosis, in one individual with CBAVD, and in one individual with allergic bronchopulmonary aspergillosis (DÃ¶rk et al. 1997; Padoan et al. 2002; Ratbi et al. 2007; Lebecque et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Residue Val1153 is located in transmembrane domain 12 of the CFTR channel, and expressing an alanine substitution at this residue in patch excised inside-out macropatches and single-channel patches from Xenopus oocytes resulted in altered pore properties and suggested that residue 1153 is located toward the intracellular side of the channel pore (Cui et al. 2012). Evidence for this variant is limited, and individuals with this variant in different molecular states have been reported with variable CFTR-related phenotypes. Therefore, the p.Val1153Glu variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 18, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 10, 2024

Variant summary: CFTR c.3458T>A (p.Val1153Glu) 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 five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250860 control chromosomes. c.3458T>A has been reported in the literature in individuals affected with Congenital absence of vas deferens and Cystic Fibrosis (Dork_1997, Ratbi_2007, Pagin_2016, McCague_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 18.7% of normal activity (Raraigh_2018). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 30888834, 26900683, 29805046, 17329263). ClinVar contains an entry for this variant (Variation ID: 53747). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.;.;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

-0.097

MutationAssessor

Pathogenic

3.5

H;.;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

D;.;.;D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.98

D;.;.;.;.

Vest4

0.97

MutPred

0.91

Gain of disorder (P = 0.0171);.;.;.;.;

MVP

1.0

MPC

0.0083

ClinPred

0.96

GERP RS

4.8

Varity_R

0.98

gMVP

0.98

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