chr7-117667005-T-A

Position:

chr7-117667005-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000492.4(CFTR):c.4340T>A(p.Val1447Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.31

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:

CFTR (HGNC:):

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11450112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4340T>A	p.Val1447Glu	missense_variant	27/27	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.4340T>A	p.Val1447Glu	missense_variant	27/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727166

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151880

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.0000726

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2

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	Aug 26, 2021	This sequence change replaces valine with glutamic acid at codon 1447 of the CFTR protein (p.Val1447Glu). The valine residue is weakly conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 01, 2019

The CFTR c.4340T>A; p.Val1447Glu variant (rs1397796355), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 455781). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 1447 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Val1447Glu variant is uncertain at this time. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.40

T;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.69

N;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.18

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

0.013

B;.;.

Vest4

0.19

MutPred

0.42

Loss of stability (P = 0.0076);.;.;

MVP

0.97

MPC

0.0032

ClinPred

0.32

GERP RS

1.7

Varity_R

0.15

gMVP

0.54

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

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