1-147758554-G-T

Variant summary

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

The NM_181703.4(GJA5):c.685C>A(p.Leu229Met) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L229L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA5 NM_181703.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.00

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 1-147758554-G-T is Pathogenic according to our data. Variant chr1-147758554-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 29666.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-147758554-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA5	NM_181703.4	c.685C>A	p.Leu229Met	missense_variant	2/2	ENST00000579774.3
LOC102723321	XR_922079.4	n.82-19007G>T		intron_variant, non_coding_transcript_variant
GJA5	NM_005266.7	c.685C>A	p.Leu229Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA5	ENST00000579774.3	c.685C>A	p.Leu229Met	missense_variant	2/2	1	NM_181703.4	P1
GJA5	ENST00000621517.1	c.685C>A	p.Leu229Met	missense_variant	2/2	2		P1
GJA5	ENST00000430508.1	c.685C>A	p.Leu229Met	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000688 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrial fibrillation, familial, 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.59
MutPred		0.78		Gain of MoRF binding (P = 0.0696);Gain of MoRF binding (P = 0.0696);Gain of MoRF binding (P = 0.0696);
MVP		0.98
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.60
gMVP		0.77

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: rs387906615; hg19: chr1-147230662;