1-147758173-G-T

Position:

• chr1-147758173-G-T

Variant summary

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

The NM_181703.4(GJA5):​c.1066C>A​(p.Leu356Ile) 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 (★). Synonymous variant affecting the same amino acid position (i.e. L356L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA5 NM_181703.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) This gene is 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 may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

ENSG00000274415 (HGNC:):

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=0.28682357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA5	NM_181703.4	c.1066C>A	p.Leu356Ile	missense_variant	2/2	ENST00000579774.3	NP_859054.1
GJA5	NM_005266.7	c.1066C>A	p.Leu356Ile	missense_variant	2/2		NP_005257.2
LOC102723321	XR_922079.4	n.82-19388G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA5	ENST00000579774.3	c.1066C>A	p.Leu356Ile	missense_variant	2/2	1	NM_181703.4	ENSP00000463851.1
GJA5	ENST00000621517.1	c.1066C>A	p.Leu356Ile	missense_variant	2/2	2		ENSP00000484552.1
ENSG00000274415	ENST00000612401.1	n.309-230G>T		intron_variant		5
ENSG00000274415	ENST00000622634.1	n.480-181G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.1066C>A (p.L356I) alteration is located in exon 2 (coding exon 1) of the GJA5 gene. This alteration results from a C to A substitution at nucleotide position 1066, causing the leucine (L) at amino acid position 356 to be replaced by an isoleucine (I). 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	0.27
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.82	D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.44	B;B
Vest4		0.34
MutPred		0.32		Loss of methylation at R352 (P = 0.1565);Loss of methylation at R352 (P = 0.1565);
MVP		0.89
ClinPred		0.36	T
GERP RS		-0.025
Varity_R		0.059
gMVP		0.12

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: chr1-147230281; COSMIC: COSV54782902; COSMIC: COSV54782902;