chr1-147758953-C-A

Position:

chr1-147758953-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2

The NM_181703.4(GJA5):c.286G>T(p.Ala96Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A96V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

GJA5
NM_181703.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 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

BS2

High AC in GnomAd4 at 27 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA5	NM_181703.4 linkuse as main transcript	c.286G>T	p.Ala96Ser	missense_variant	2/2	ENST00000579774.3	NP_859054.1	P36382X5D2H9
GJA5	NM_005266.7 linkuse as main transcript	c.286G>T	p.Ala96Ser	missense_variant	2/2		NP_005257.2	P36382X5D2H9
LOC102723321	XR_922079.4 linkuse as main transcript	n.82-18608C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJA5	ENST00000579774.3 linkuse as main transcript	c.286G>T	p.Ala96Ser	missense_variant	2/2	1	NM_181703.4	ENSP00000463851.1	P36382
GJA5	ENST00000621517.1 linkuse as main transcript	c.286G>T	p.Ala96Ser	missense_variant	2/2	2		ENSP00000484552.1	P36382
GJA5	ENST00000430508.1 linkuse as main transcript	c.286G>T	p.Ala96Ser	missense_variant	2/2	2		ENSP00000407645.1	A0A0B4J1Y3

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251188

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135726

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:

0.0000924

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000315

AC:

460

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000936

Gnomad4 NFE exome

AF:

0.000397

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000177

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.000367

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 11

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 22, 2006

- -

Atrial fibrillation, familial, 11;C4551959:Atrial standstill 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 96 of the GJA5 protein (p.Ala96Ser). This variant is present in population databases (rs121434557, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of GJA5-related conditions (PMID: 16790700, 24144883, 28074886, 30847666). ClinVar contains an entry for this variant (Variation ID: 16998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJA5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJA5 function (PMID: 16790700, 24060583, 26503720, 28457700). 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. -

Atrial fibrillation

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lildballe Lab, Aarhus University Hospital

Mar 01, 2024

PM2(s), BS2(s), PP3(s) -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2024

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23292621, 28074886, 21597036, 26503720, 16790700, 24656738, 23040431, 28457700, 24626989, 9588401, 33664309, 31589614, 34697415, 27374306, 24060583, 24144883, 30847666) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

.;.;N

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

.;.;D

Sift4G

Uncertain

0.016

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.80

MVP

0.98

ClinPred

0.51

GERP RS

4.7

Varity_R

0.48

gMVP

0.86

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