Genetic Variant GJA4:p.Arg132Ser (chr1-34794607-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002060.3(GJA4):c.394C>A(p.Arg132Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132C) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.75

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18951851).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002060.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA4	NM_002060.3	MANE Select	c.394C>A	p.Arg132Ser	missense	Exon 2 of 2	NP_002051.2	P35212

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJA4	ENST00000342280.5	TSL:1 MANE Select	c.394C>A	p.Arg132Ser	missense	Exon 2 of 2	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1	TSL:1	n.207+61164G>T		intron	N/A	ENSP00000429902.1	E5RH51
GJA4	ENST00000868038.1		c.394C>A	p.Arg132Ser	missense	Exon 2 of 2	ENSP00000538097.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111860

Other (OTH)

AF:

0.00

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.39

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.045

MutationAssessor

Benign

1.4

PhyloP100

3.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.15

REVEL

Uncertain

0.39

Sift

Benign

0.63

Sift4G

Benign

0.49

Polyphen

0.039

Vest4

0.12

MutPred

0.48

Loss of MoRF binding (P = 0.0076)

MVP

0.96

MPC

0.55

ClinPred

0.32

GERP RS

4.1

Varity_R

0.16

gMVP

0.57

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over