Variant chr1-147758986-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_181703.4(GJA5):c.253G>A(p.Val85Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V85V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

GJA5
NM_181703.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

GJA5 links:

LOC102723321 (HGNC:):

LOC102723321 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity CXA5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_181703.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 1-147758986-C-T is Pathogenic according to our data. Variant chr1-147758986-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29664.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-147758986-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GJA5	NM_181703.4 linkuse as main transcript	c.253G>A	p.Val85Ile	missense_variant	2/2	ENST00000579774.3
LOC102723321	XR_922079.4 linkuse as main transcript	n.82-18575C>T		intron_variant, non_coding_transcript_variant
GJA5	NM_005266.7 linkuse as main transcript	c.253G>A	p.Val85Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GJA5	ENST00000579774.3 linkuse as main transcript	c.253G>A	p.Val85Ile	missense_variant	2/2	1	NM_181703.4	P1
GJA5	ENST00000621517.1 linkuse as main transcript	c.253G>A	p.Val85Ile	missense_variant	2/2	2		P1
GJA5	ENST00000430508.1 linkuse as main transcript	c.253G>A	p.Val85Ile	missense_variant	2/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 11

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.0

.;.;N

REVEL

Pathogenic

0.88

Sift

Benign

0.11

.;.;T

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.86

MutPred

0.84

Gain of catalytic residue at L90 (P = 0.0176);Gain of catalytic residue at L90 (P = 0.0176);Gain of catalytic residue at L90 (P = 0.0176);

MVP

0.99

ClinPred

0.96

GERP RS

5.8

Varity_R

0.47

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

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