Variant 1-34794599-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002060.3(GJA4):c.386C>A(p.Ala129Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,453,802 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: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.362

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:

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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=0.124345124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3 linkuse as main transcript	c.386C>A	p.Ala129Asp	missense_variant	2/2	ENST00000342280.5	NP_002051.2	P35212
GJA4	XM_005270750.3 linkuse as main transcript	c.386C>A	p.Ala129Asp	missense_variant	2/2		XP_005270807.1	P35212
GJA4	XM_017001043.3 linkuse as main transcript	c.386C>A	p.Ala129Asp	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.386C>A	p.Ala129Asp	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1 linkuse as main transcript	n.207+61172G>T		intron_variant		1		ENSP00000429902.1	E5RH51
GJA4	ENST00000450137.1 linkuse as main transcript	c.386C>A	p.Ala129Asp	missense_variant	2/2	2		ENSP00000409186.1	Q5JW71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000820

AC:

AN:

243800

Hom.:

AF XY:

0.00000755

AC XY:

AN XY:

132504

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000619

AC:

AN:

1453802

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723522

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:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.386C>A (p.A129D) alteration is located in exon 2 (coding exon 1) of the GJA4 gene. This alteration results from a C to A substitution at nucleotide position 386, causing the alanine (A) at amino acid position 129 to be replaced by an aspartic acid (D). 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

Benign

0.10

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.32

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.086

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.27

Sift

Benign

0.64

T;T

Sift4G

Benign

0.62

T;T

Polyphen

0.0010

B;B

Vest4

0.17

MutPred

0.43

Loss of MoRF binding (P = 0.0674);Loss of MoRF binding (P = 0.0674);

MVP

0.90

MPC

0.73

ClinPred

0.047

GERP RS

4.2

Varity_R

0.12

gMVP

0.53

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