1-34794654-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.140
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]
SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
GJA4NM_002060.3 linkc.441C>G p.Ile147Met missense_variant Exon 2 of 2 ENST00000342280.5 NP_002051.2 P35212
GJA4XM_005270750.3 linkc.441C>G p.Ile147Met missense_variant Exon 2 of 2 XP_005270807.1 P35212
GJA4XM_017001043.3 linkc.441C>G p.Ile147Met missense_variant Exon 2 of 2 XP_016856532.1 P35212

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJA4ENST00000342280.5 linkc.441C>G p.Ile147Met missense_variant Exon 2 of 2 1 NM_002060.3 ENSP00000343676.4 P35212
SMIM12ENST00000426886.1 linkn.207+61117G>C intron_variant Intron 2 of 4 1 ENSP00000429902.1 E5RH51
GJA4ENST00000450137.1 linkc.441C>G p.Ile147Met missense_variant Exon 2 of 2 2 ENSP00000409186.1 Q5JW71

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
LINK: link

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; API