rs121434558

chr1-147758977-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_181703.4(GJA5):c.262C>T(p.Pro88Ser) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA5 NM_181703.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.99

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity CXA5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_181703.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-147758977-G-A is Pathogenic according to our data. Variant chr1-147758977-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16999.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-147758977-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA5	NM_181703.4	c.262C>T	p.Pro88Ser	missense_variant	2/2	ENST00000579774.3
LOC102723321	XR_922079.4	n.82-18584G>A		intron_variant, non_coding_transcript_variant
GJA5	NM_005266.7	c.262C>T	p.Pro88Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA5	ENST00000579774.3	c.262C>T	p.Pro88Ser	missense_variant	2/2	1	NM_181703.4	P1
GJA5	ENST00000621517.1	c.262C>T	p.Pro88Ser	missense_variant	2/2	2		P1
GJA5	ENST00000430508.1	c.262C>T	p.Pro88Ser	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrial fibrillation, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 22, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.85
MutPred		0.90		Gain of catalytic residue at P88 (P = 0.0208);Gain of catalytic residue at P88 (P = 0.0208);Gain of catalytic residue at P88 (P = 0.0208);
MVP		0.99
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		1.0

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: rs121434558; hg19: chr1-147231085;