Variant 1-34794911-G-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.698G>A(p.Cys233Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.000015 ( 0 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64

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=0.24019656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3 linkuse as main transcript	c.698G>A	p.Cys233Tyr	missense_variant	2/2	ENST00000342280.5	NP_002051.2	P35212
GJA4	XM_005270750.3 linkuse as main transcript	c.698G>A	p.Cys233Tyr	missense_variant	2/2		XP_005270807.1	P35212
GJA4	XM_017001043.3 linkuse as main transcript	c.698G>A	p.Cys233Tyr	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.698G>A	p.Cys233Tyr	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1 linkuse as main transcript	n.207+60860C>T		intron_variant		1		ENSP00000429902.1	E5RH51
GJA4	ENST00000450137.1 linkuse as main transcript	c.698G>A	p.Cys233Tyr	missense_variant	2/2	2		ENSP00000409186.1	Q5JW71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251288

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135820

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727242

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:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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 11, 2023

The c.698G>A (p.C233Y) alteration is located in exon 2 (coding exon 1) of the GJA4 gene. This alteration results from a G to A substitution at nucleotide position 698, causing the cysteine (C) at amino acid position 233 to be replaced by a tyrosine (Y). 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

0.13

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Uncertain

0.57

D;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.39

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

0.94

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.23

T;T

Sift4G

Benign

0.96

T;T

Polyphen

0.0010

B;B

Vest4

0.17

MutPred

0.45

Gain of MoRF binding (P = 0.0838);Gain of MoRF binding (P = 0.0838);

MVP

0.86

MPC

0.82

ClinPred

0.040

GERP RS

2.2

Varity_R

0.15

gMVP

0.68

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