1-34794654-C-G

Variant names:

• chr1-34794654-C-G
• NM_002060.3:c.441C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002060.3(GJA4):​c.441C>G​(p.Ile147Met) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I147V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA4 NM_002060.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.140

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42350835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA4	NM_002060.3	c.441C>G	p.Ile147Met	missense_variant	Exon 2 of 2	ENST00000342280.5	NP_002051.2
GJA4	XM_005270750.3	c.441C>G	p.Ile147Met	missense_variant	Exon 2 of 2		XP_005270807.1
GJA4	XM_017001043.3	c.441C>G	p.Ile147Met	missense_variant	Exon 2 of 2		XP_016856532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA4	ENST00000342280.5	c.441C>G	p.Ile147Met	missense_variant	Exon 2 of 2	1	NM_002060.3	ENSP00000343676.4
SMIM12	ENST00000426886.1	n.207+61117G>C		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
GJA4	ENST00000450137.1	c.441C>G	p.Ile147Met	missense_variant	Exon 2 of 2	2		ENSP00000409186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.441C>G (p.I147M) alteration is located in exon 2 (coding exon 1) of the GJA4 gene. This alteration results from a C to G substitution at nucleotide position 441, causing the isoleucine (I) at amino acid position 147 to be replaced by a methionine (M). 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	0.33
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	18
DANN	Benign	0.62
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.58	T;T
Sift4G	Benign	0.38	T;T
Polyphen		1.0	D;B
Vest4		0.24
MutPred		0.48		Gain of disorder (P = 0.067);Gain of disorder (P = 0.067);
MVP		0.95
MPC		1.3
ClinPred		0.61	D
GERP RS		4.5
Varity_R		0.25
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-35260255;