rs104893964

Positions:

• chr6-121446912-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000165.5(GJA1):​c.65G>A​(p.Gly22Glu) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

Genes affected

GJA1 (HGNC:4274): (gap junction protein alpha 1) 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. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 17) in uniprot entity CXA1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000165.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GJA1. . Gene score misZ 1.2784 (greater than the threshold 3.09). Trascript score misZ 3.3775 (greater than threshold 3.09). GenCC has associacion of gene with craniometaphyseal dysplasia, autosomal recessive, Hallermann-Streiff syndrome, syndactyly type 3, oculodentodigital dysplasia, nonsyndromic genetic hearing loss, hypoplastic left heart syndrome 1, autosomal dominant palmoplantar keratoderma and congenital alopecia, oculodentodigital dysplasia, autosomal recessive, craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva 3, erythrokeratodermia variabilis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 6-121446912-G-A is Pathogenic according to our data. Variant chr6-121446912-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16985.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA1	NM_000165.5	c.65G>A	p.Gly22Glu	missense_variant	2/2	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.65G>A	p.Gly22Glu	missense_variant	2/2	1	NM_000165.5	ENSP00000282561	P1
GJA1	ENST00000647564.1	c.65G>A	p.Gly22Glu	missense_variant	2/2			ENSP00000497565	P1
GJA1	ENST00000649003.1	c.65G>A	p.Gly22Glu	missense_variant	2/2			ENSP00000497283	P1
GJA1	ENST00000650427.1	c.65G>A	p.Gly22Glu	missense_variant	2/2			ENSP00000497367	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Oculodentodigital dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Oculodentodigital dysplasia, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 22 of the GJA1 protein (p.Gly22Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with oculodentodigital dysplasia (ODDD) (PMID: 19338053, 32318302). ClinVar contains an entry for this variant (Variation ID: 16985). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Gly22 amino acid residue in GJA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19338053; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.8	.;.;D;.;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.97
MutPred		0.99		Gain of ubiquitination at K23 (P = 0.0513);Gain of ubiquitination at K23 (P = 0.0513);Gain of ubiquitination at K23 (P = 0.0513);Gain of ubiquitination at K23 (P = 0.0513);Gain of ubiquitination at K23 (P = 0.0513);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.98
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: rs104893964; hg19: chr6-121768058; COSMIC: COSV99246715;