rs1764391

Positions:

• chr1-34795168-C-G
• chr1-34795168-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002060.3(GJA4):​c.955C>G​(p.Pro319Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. P319S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GJA4 NM_002060.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296

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]

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038024426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3	c.955C>G	p.Pro319Ala	missense_variant	2/2	ENST00000342280.5	NP_002051.2
GJA4	XM_005270750.3	c.955C>G	p.Pro319Ala	missense_variant	2/2		XP_005270807.1
GJA4	XM_017001043.3	c.955C>G	p.Pro319Ala	missense_variant	2/2		XP_016856532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA4	ENST00000342280.5	c.955C>G	p.Pro319Ala	missense_variant	2/2	1	NM_002060.3	ENSP00000343676	P1
SMIM12	ENST00000426886.1	c.207+60603G>C		intron_variant, NMD_transcript_variant		1		ENSP00000429902

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	1.1
DANN	Benign	0.52
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.038	T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.26
Sift	Benign	0.36	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.091
MutPred		0.19		Loss of catalytic residue at P319 (P = 0.0193);
MVP		0.73
MPC		0.47
ClinPred		0.10	T
GERP RS		0.013
Varity_R		0.028
gMVP		0.38

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

Other links and lift over

dbSNP: rs1764391; hg19: chr1-35260769;