1-34794682-G-A

Position:

chr1-34794682-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002060.3(GJA4):c.469G>A(p.Ala157Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,611,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.158

Variant links:

Genes affected

GJA4 (HGNC:4278): (gap junction protein alpha 4) This gene encodes 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 have been associated with atherosclerosis and a higher risk of myocardial infarction. [provided by RefSeq, Jul 2008]

GJA4 links:

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17517376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3 linkuse as main transcript	c.469G>A	p.Ala157Thr	missense_variant	2/2	ENST00000342280.5	NP_002051.2	P35212
GJA4	XM_005270750.3 linkuse as main transcript	c.469G>A	p.Ala157Thr	missense_variant	2/2		XP_005270807.1	P35212
GJA4	XM_017001043.3 linkuse as main transcript	c.469G>A	p.Ala157Thr	missense_variant	2/2		XP_016856532.1	P35212

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJA4	ENST00000342280.5 linkuse as main transcript	c.469G>A	p.Ala157Thr	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1 linkuse as main transcript	n.207+61089C>T		intron_variant		1		ENSP00000429902.1	E5RH51
GJA4	ENST00000450137.1 linkuse as main transcript	c.469G>A	p.Ala157Thr	missense_variant	2/2	2		ENSP00000409186.1	Q5JW71

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000521

AC:

AN:

249322

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134940

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

AN:

1459242

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

726000

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:

0.00

Gnomad4 NFE exome

AF:

0.0000603

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000614

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Jan 23, 2024

The GJA4 c.469G>A (p.Ala157Thr) variant was identified at a near heterozygous allele fraction of 41%, a frequency which may be consistent with it being of germline origin. Computational predictors are uncertain as to the impact of this variant on GJA4 function. This variant is observed in 73/1,611,396 alleles in the general population (gnomAD v4.0.0). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the GJA4 c.469G>A (p.Ala157Thr) variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.24

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.18

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.12

N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.060

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.41

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.0

B;B

Vest4

0.12

MVP

0.88

MPC

0.47

ClinPred

0.026

GERP RS

2.5

Varity_R

0.086

gMVP

0.47

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