rs781831348

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The ENST00000579774.3(GJA5):c.365C>T(p.Ser122Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. S122C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

GJA5
ENST00000579774.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.98

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27804503).

BS2

High AC in GnomAd4 at 8 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GJA5	NM_181703.4 linkuse as main transcript	c.365C>T	p.Ser122Phe	missense_variant	2/2	ENST00000579774.3	NP_859054.1
LOC102723321	XR_922079.4 linkuse as main transcript	n.82-18687G>A		intron_variant, non_coding_transcript_variant
GJA5	NM_005266.7 linkuse as main transcript	c.365C>T	p.Ser122Phe	missense_variant	2/2		NP_005257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GJA5	ENST00000579774.3 linkuse as main transcript	c.365C>T	p.Ser122Phe	missense_variant	2/2	1	NM_181703.4	ENSP00000463851	P1
GJA5	ENST00000621517.1 linkuse as main transcript	c.365C>T	p.Ser122Phe	missense_variant	2/2	2		ENSP00000484552	P1
GJA5	ENST00000430508.1 linkuse as main transcript	c.365C>T	p.Ser122Phe	missense_variant	2/2	2		ENSP00000407645

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251150

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.0000612

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2024

The c.365C>T (p.S122F) alteration is located in exon 2 (coding exon 1) of the GJA5 gene. This alteration results from a C to T substitution at nucleotide position 365, causing the serine (S) at amino acid position 122 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 122 of the GJA5 protein (p.Ser122Phe). This variant is present in population databases (rs781831348, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GJA5-related conditions. ClinVar contains an entry for this variant (Variation ID: 539329). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.70

D;D;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.63

.;T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Uncertain

-0.0036

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.4

.;.;N

REVEL

Benign

0.27

Sift

Benign

0.045

.;.;D

Sift4G

Uncertain

0.042

D;D;.

Polyphen

0.010

B;B;.

Vest4

0.16

MutPred

0.39

Loss of disorder (P = 0.0028);Loss of disorder (P = 0.0028);Loss of disorder (P = 0.0028);

MVP

0.86

ClinPred

0.15

GERP RS

2.9

Varity_R

0.083

gMVP

0.58

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