NM_181703.4:c.223A>T

Variant names:

• chr1-147759016-T-A
• rs587777304
• NM_181703.4:c.223A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181703.4(GJA5):​c.223A>T​(p.Ile75Phe) 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. 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. I75S) 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 P:1 U:1
• Conservation: PhyloP100: 4.94

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]

LOC102723321 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA5	NM_181703.4	c.223A>T	p.Ile75Phe	missense_variant	Exon 2 of 2	ENST00000579774.3	NP_859054.1
GJA5	NM_005266.7	c.223A>T	p.Ile75Phe	missense_variant	Exon 2 of 2		NP_005257.2
LOC102723321	XR_922079.4	n.82-18545T>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA5	ENST00000579774.3	c.223A>T	p.Ile75Phe	missense_variant	Exon 2 of 2	1	NM_181703.4	ENSP00000463851.1
GJA5	ENST00000621517.1	c.223A>T	p.Ile75Phe	missense_variant	Exon 2 of 2	2		ENSP00000484552.1
GJA5	ENST00000430508.1	c.223A>T	p.Ile75Phe	missense_variant	Exon 2 of 2	2		ENSP00000407645.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial fibrillation, familial, 11 Pathogenic:1

Apr 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Atrial fibrillation, familial, 11;C4551959:Atrial standstill 1 Uncertain:1

Aug 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects GJA5 function (PMID: 23348765). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 126903). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 23348765). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 75 of the GJA5 protein (p.Ile75Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	.;.;D
REVEL	Pathogenic	0.86
Sift	Benign	0.039	.;.;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.83	P;P;.
Vest4		0.49
MutPred		0.64		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.39
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

LitVar

Other links and lift over

dbSNP: rs587777304; hg19: chr1-147231124;