Genetic Variant GJA4:p.Ile147Val (chr1-34794652-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002060.3(GJA4):c.439A>G(p.Ile147Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,608,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I147M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA4	NM_002060.3 link	c.439A>G	p.Ile147Val	missense_variant	Exon 2 of 2	ENST00000342280.5	NP_002051.2	P35212
GJA4	XM_005270750.3 link	c.439A>G	p.Ile147Val	missense_variant	Exon 2 of 2		XP_005270807.1	P35212
GJA4	XM_017001043.3 link	c.439A>G	p.Ile147Val	missense_variant	Exon 2 of 2		XP_016856532.1	P35212

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJA4	ENST00000342280.5 link	c.439A>G	p.Ile147Val	missense_variant	Exon 2 of 2	1	NM_002060.3	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1 link	n.207+61119T>C		intron_variant	Intron 2 of 4	1		ENSP00000429902.1	E5RH51
GJA4	ENST00000450137.1 link	c.439A>G	p.Ile147Val	missense_variant	Exon 2 of 2	2		ENSP00000409186.1	Q5JW71

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247496

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134078

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:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1456044

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724526

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.439A>G (p.I147V) alteration is located in exon 2 (coding exon 1) of the GJA4 gene. This alteration results from a A to G substitution at nucleotide position 439, causing the isoleucine (I) at amino acid position 147 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.82

N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.96

D;P

Vest4

0.33

MVP

0.95

MPC

0.87

ClinPred

0.71

GERP RS

5.5

Varity_R

0.50

gMVP

0.69

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