rs121434557

chr1-147758953-C-Achr1-147758953-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 6.17

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]

LOC102723321 (HGNC:):

ACMG classification

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 GnomAd at 27 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA5	NM_181703.4	c.286G>T	p.Ala96Ser	missense_variant	2/2	ENST00000579774.3
LOC102723321	XR_922079.4	n.82-18608C>A		intron_variant, non_coding_transcript_variant
GJA5	NM_005266.7	c.286G>T	p.Ala96Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA5	ENST00000579774.3	c.286G>T	p.Ala96Ser	missense_variant	2/2	1	NM_181703.4	P1
GJA5	ENST00000621517.1	c.286G>T	p.Ala96Ser	missense_variant	2/2	2		P1
GJA5	ENST00000430508.1	c.286G>T	p.Ala96Ser	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152216 Hom.: 0 Cov.: 32

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: 30 AN: 251188 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135726

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.: 1 Cov.: 33 AF XY: 0.000300 AC XY: 218 AN XY: 727214

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: 27 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74484

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.: 0

Bravo AF: 0.000200

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 06, 2021

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in reduced cell-cell coupling and connexin 40 activity and mice that are heterozygous for the A96S variant exhibit significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation (Gollob et al., 2006; Lbkemeier et al., 2013); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 16998; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23292621, 28074886, 24144883, 21597036, 26503720, 16790700, 24656738, 23040431, 28457700, 24626989, 9588401, 24060583, 26582918, 33664309, 30847666, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	24
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	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.60	T
Sift4G	Uncertain	0.016	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.80
MVP		0.98
ClinPred		0.51	D
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

Other links and lift over

dbSNP: rs121434557; hg19: chr1-147231061; COSMIC: COSV99053976; COSMIC: COSV99053976;