rs962041031

chr6-121447290-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000165.5(GJA1):c.443G>A(p.Arg148Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.78

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000165.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GJA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 6-121447290-G-A is Pathogenic according to our data. Variant chr6-121447290-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435324.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr6-121447290-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA1	NM_000165.5	c.443G>A	p.Arg148Gln	missense_variant	2/2	ENST00000282561.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA1	ENST00000282561.4	c.443G>A	p.Arg148Gln	missense_variant	2/2	1	NM_000165.5	P1
GJA1	ENST00000647564.1	c.443G>A	p.Arg148Gln	missense_variant	2/2			P1
GJA1	ENST00000649003.1	c.443G>A	p.Arg148Gln	missense_variant	2/2			P1
GJA1	ENST00000650427.1	c.443G>A	p.Arg148Gln	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	Published functional studies demonstrate improper protein localization and impaired ability to form functional gap junctions (Zheng et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36142674, 14729836, 34502077, 32318302, 21871435, 32676758, 31023660, 18946008, 19338053, 35023121, 33080786) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Oculodentodigital dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 15, 2015

- -

Oculodentodigital dysplasia, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA1 function (PMID: 33080786). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJA1 protein function. ClinVar contains an entry for this variant (Variation ID: 435324). This missense change has been observed in individuals with autosomal dominant oculodentodigital dysplasia (PMID: 14729836, 33080786, 35023121). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GJA1 protein (p.Arg148Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;D;D;D
Eigen	Benign	0.027
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.6	L;L;L;L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
Polyphen		0.77	P;P;P;P;P
Vest4		0.36
MutPred		0.84		Loss of methylation at R148 (P = 0.012);Loss of methylation at R148 (P = 0.012);Loss of methylation at R148 (P = 0.012);Loss of methylation at R148 (P = 0.012);Loss of methylation at R148 (P = 0.012);
MVP		0.98
MPC		0.58
ClinPred		0.88	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.83

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: rs962041031; hg19: chr6-121768436; COSMIC: COSV56998562;