Variant chr1-34794442-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002060.3(GJA4):c.229T>C(p.Tyr77His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3 linkuse as main transcript	c.229T>C	p.Tyr77His	missense_variant	2/2	ENST00000342280.5	NP_002051.2	P35212
GJA4	XM_005270750.3 linkuse as main transcript	c.229T>C	p.Tyr77His	missense_variant	2/2		XP_005270807.1	P35212
GJA4	XM_017001043.3 linkuse as main transcript	c.229T>C	p.Tyr77His	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.229T>C	p.Tyr77His	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1 linkuse as main transcript	n.207+61329A>G		intron_variant		1		ENSP00000429902.1	E5RH51
GJA4	ENST00000450137.1 linkuse as main transcript	c.229T>C	p.Tyr77His	missense_variant	2/2	2		ENSP00000409186.1	Q5JW71

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251376

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Mar 20, 2024

The c.229T>C (p.Y77H) alteration is located in exon 2 (coding exon 1) of the GJA4 gene. This alteration results from a T to C substitution at nucleotide position 229, causing the tyrosine (Y) at amino acid position 77 to be replaced by a histidine (H). 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

0.98

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.63

MutPred

0.78

Loss of stability (P = 0.0606);Loss of stability (P = 0.0606);

MVP

0.98

MPC

1.6

ClinPred

0.86

GERP RS

5.5

Varity_R

0.94

gMVP

0.98

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