rs397508567

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PP2PP3_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1153M) has been classified as Uncertain significance.

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:3U:4O:1

Conservation

PhyloP100: 6.10

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
congenital bilateral absence of vas deferens
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary chronic pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFTR links:

ENSG00000083622 (HGNC:40145):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000492.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

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 VariationId is 53747.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3458T>A	p.Val1153Glu	missense_variant	Exon 21 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS2	NR_199597.1 link	n.177+1526A>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3458T>A	p.Val1153Glu	missense_variant	Exon 21 of 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

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250860

AF XY:

0.0000221

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 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

African (AFR)

AF:

0.0000300

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

1107310

Other (OTH)

AF:

0.00

AC:

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68006

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:3Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:2Other:1

Mar 20, 2025

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VarIant NM_000492.4(CFTR):c.3458T>A (p.Val1153Glu) has GnomAD 4.1 frequency of 0.00003419 with 0 homozygote. Reported as likely pathogenic in PMID 29805046 -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). In another assay testing CFTR function, this variant showed a functionally abnormal result (Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). 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. -

CFTR-related disorder

Pathogenic:1

Jan 29, 2018

CFTR-France

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Mar 18, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 27, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Three 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 approximately 18% of normal activity (Raraigh_2018, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 39151434, 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

Aug 06, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.;.

PhyloP100

6.1

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

PromoterAI

-0.0044

Neutral

(source)

Varity_R

0.98

gMVP

0.98

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over