1-34794571-G-T

Position:

• chr1-34794571-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002060.3(GJA4):​c.358G>T​(p.Asp120Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA4 NM_002060.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3	c.358G>T	p.Asp120Tyr	missense_variant	2/2	ENST00000342280.5	NP_002051.2
GJA4	XM_005270750.3	c.358G>T	p.Asp120Tyr	missense_variant	2/2		XP_005270807.1
GJA4	XM_017001043.3	c.358G>T	p.Asp120Tyr	missense_variant	2/2		XP_016856532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA4	ENST00000342280.5	c.358G>T	p.Asp120Tyr	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4
SMIM12	ENST00000426886.1	n.207+61200C>A		intron_variant		1		ENSP00000429902.1
GJA4	ENST00000450137.1	c.358G>T	p.Asp120Tyr	missense_variant	2/2	2		ENSP00000409186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.358G>T (p.D120Y) alteration is located in exon 2 (coding exon 1) of the GJA4 gene. This alteration results from a G to T substitution at nucleotide position 358, causing the aspartic acid (D) at amino acid position 120 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	0.21
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.084	T;T
Polyphen		1.0	D;D
Vest4		0.49
MutPred		0.41		Gain of MoRF binding (P = 0.0399);Gain of MoRF binding (P = 0.0399);
MVP		0.93
MPC		1.4
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.23
gMVP		0.86

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: chr1-35260172;