Variant 1-147758953-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_181703.4(GJA5):c.286G>A(p.Ala96Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A96S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GJA5
NM_181703.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

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:

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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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-147758953-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA5	NM_181703.4 linkuse as main transcript	c.286G>A	p.Ala96Thr	missense_variant	2/2	ENST00000579774.3	NP_859054.1	P36382X5D2H9
GJA5	NM_005266.7 linkuse as main transcript	c.286G>A	p.Ala96Thr	missense_variant	2/2		NP_005257.2	P36382X5D2H9
LOC102723321	XR_922079.4 linkuse as main transcript	n.82-18608C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJA5	ENST00000579774.3 linkuse as main transcript	c.286G>A	p.Ala96Thr	missense_variant	2/2	1	NM_181703.4	ENSP00000463851.1	P36382
GJA5	ENST00000621517.1 linkuse as main transcript	c.286G>A	p.Ala96Thr	missense_variant	2/2	2		ENSP00000484552.1	P36382
GJA5	ENST00000430508.1 linkuse as main transcript	c.286G>A	p.Ala96Thr	missense_variant	2/2	2		ENSP00000407645.1	A0A0B4J1Y3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727214

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

.;.;N

REVEL

Pathogenic

0.79

Sift

Uncertain

0.026

.;.;D

Sift4G

Benign

0.13

T;T;.

Polyphen

0.97

D;D;.

Vest4

0.49

MutPred

0.65

Gain of glycosylation at A96 (P = 0.0331);Gain of glycosylation at A96 (P = 0.0331);Gain of glycosylation at A96 (P = 0.0331);

MVP

0.98

ClinPred

0.87

GERP RS

4.7

Varity_R

0.43

gMVP

0.89

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over