rs1554201018

Positions:

• chr6-121447259-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000165.5(GJA1):​c.412G>A​(p.Gly138Ser) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G138R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 topological_domain Cytoplasmic (size 57) in uniprot entity CXA1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000165.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.919
• PP5: Variant 6-121447259-G-A is Pathogenic according to our data. Variant chr6-121447259-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 537756.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.412G>A	p.Gly138Ser	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.412G>A	p.Gly138Ser	missense_variant	2/2	1	NM_000165.5	ENSP00000282561.3
GJA1	ENST00000647564.1	c.412G>A	p.Gly138Ser	missense_variant	2/2			ENSP00000497565.1
GJA1	ENST00000649003.1	c.412G>A	p.Gly138Ser	missense_variant	2/2			ENSP00000497283.1
GJA1	ENST00000650427.1	c.412G>A	p.Gly138Ser	missense_variant	2/2			ENSP00000497367.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculodentodigital dysplasia, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly138 amino acid residue in GJA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19338053, 18003637, 27226478, 18946008, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with autosomal dominant oculodentodigital dysplasia (PMID: 18946008, 25388818, 19338053). ClinVar contains an entry for this variant (Variation ID: 537756). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 138 of the GJA1 protein (p.Gly138Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	23
DANN	Benign	0.90
DEOGEN2	Uncertain	0.56	D;D;D;D;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;.;.;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.3	L;L;L;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.030	.;.;N;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.57	.;.;T;.;.
Sift4G	Benign	0.48	.;.;T;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.91
MutPred		0.76		Gain of phosphorylation at G138 (P = 0.0485);Gain of phosphorylation at G138 (P = 0.0485);Gain of phosphorylation at G138 (P = 0.0485);Gain of phosphorylation at G138 (P = 0.0485);Gain of phosphorylation at G138 (P = 0.0485);
MVP		0.98
MPC		0.53
ClinPred		0.55	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.89

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: rs1554201018; hg19: chr6-121768405; COSMIC: COSV56997598;