chr1-147908097-G-A

Position:

• chr1-147908097-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005267.5(GJA8):​c.142G>A​(p.Glu48Lys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.07

Genes affected

GJA8 (HGNC:4281): (gap junction protein alpha 8) This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Extracellular (size 28) in uniprot entity CXA8_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_005267.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA8	NM_005267.5	c.142G>A	p.Glu48Lys	missense_variant	2/2	ENST00000369235.2	NP_005258.2
GJA8	XM_011509417.3	c.142G>A	p.Glu48Lys	missense_variant	1/2		XP_011507719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA8	ENST00000369235.2	c.142G>A	p.Glu48Lys	missense_variant	2/2		NM_005267.5	ENSP00000358238	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 1 multiple types Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1999	- -
Uncertain significance, criteria provided, single submitter	curation	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	Jan 21, 2023	Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Moderate), PM1(Supporting), PM2(Supporting), PP3. Original variant report: PMID:10480374. The cataract phenotype reported for this variant is: Pulverulent nuclear and zonular. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.97		Gain of ubiquitination at E48 (P = 0.0117);
MVP		0.96
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
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: rs80358201; hg19: chr1-147380224;