1-34794334-G-T

Position:

• chr1-34794334-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002060.3(GJA4):​c.121G>T​(p.Gly41Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA4 NM_002060.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:4
• Conservation: PhyloP100: 8.08

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 1-34794334-G-T is Pathogenic according to our data. Variant chr1-34794334-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 996750.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3	c.121G>T	p.Gly41Cys	missense_variant	2/2	ENST00000342280.5	NP_002051.2
GJA4	XM_005270750.3	c.121G>T	p.Gly41Cys	missense_variant	2/2		XP_005270807.1
GJA4	XM_017001043.3	c.121G>T	p.Gly41Cys	missense_variant	2/2		XP_016856532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA4	ENST00000342280.5	c.121G>T	p.Gly41Cys	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4
SMIM12	ENST00000426886.1	n.207+61437C>A		intron_variant		1		ENSP00000429902.1
GJA4	ENST00000450137.1	c.121G>T	p.Gly41Cys	missense_variant	2/2	2		ENSP00000409186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: no assertion criteria provided

Submissions by phenotype

Hepatic hemangioma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Apr 08, 2021	- -
Pathogenic, no assertion criteria provided	research	Keith Choate Laboratory, Yale University	Dec 24, 2020	The Gly41Cys variant in Cx37 was identified in hepatic hemangioma tissue from 12 unrelated patients. This variant was absent in normal liver tissue from the same respective individuals and was absent from 251,000 sequenced alleles in the gnomAD database. Further, in vitro functional studies demonstrate that the Gly41Cys variant leads to activation of SGK1, a serine/threonine kinase, via serine 78 phosphorylation. -

Cutaneous venous malformation Pathogenic:1

Pathogenic, no assertion criteria provided

research

Keith Choate Laboratory, Yale University

Dec 24, 2020

The Gly41Cys variant in Cx37 was identified in cutaneous venous malformations in 3 unrelated individuals. This variant was absent in normal tissue from the same respective individuals and was absent from 251,000 sequenced alleles in the gnomAD database. Further, in vitro functional studies demonstrate that the Gly41Cys variant leads to activation of SGK1, a serine/threonine kinase, via serine 78 phosphorylation. -

Skin hemangioma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Apr 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.73		Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);
MVP		0.99
MPC		1.4
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.56
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-35259935;