rs1057518872

Variant names:

• chr6-121447287-T-C
• rs1057518872
• NM_000165.5:c.440T>C

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.440T>C​(p.Met147Thr) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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
• PP2: Missense variant in the GJA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2784 (below the threshold of 3.09). Trascript score misZ: 3.3775 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.961
• PP5: Variant 6-121447287-T-C is Pathogenic according to our data. Variant chr6-121447287-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 374068.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA1	NM_000165.5	c.440T>C	p.Met147Thr	missense_variant	Exon 2 of 2	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.440T>C	p.Met147Thr	missense_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3
GJA1	ENST00000647564.1	c.440T>C	p.Met147Thr	missense_variant	Exon 2 of 2			ENSP00000497565.1
GJA1	ENST00000649003.1	c.440T>C	p.Met147Thr	missense_variant	Exon 2 of 2			ENSP00000497283.1
GJA1	ENST00000650427.1	c.440T>C	p.Met147Thr	missense_variant	Exon 2 of 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

Anteverted nares;C1843496:Bilateral microphthalmos;C3714756:Intellectual disability;C4021254:Cutaneous finger syndactyly Pathogenic:1

Jul 02, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;D;D;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	.;.;.;.;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.5	M;M;M;M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.9	.;.;D;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	.;.;D;.;.
Sift4G	Uncertain	0.0070	.;.;D;.;.
Polyphen		0.98	D;D;D;D;D
Vest4		0.92
MutPred		0.83		Loss of stability (P = 0.0263);Loss of stability (P = 0.0263);Loss of stability (P = 0.0263);Loss of stability (P = 0.0263);Loss of stability (P = 0.0263);
MVP		1.0
MPC		1.3
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.69
gMVP		0.94

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: rs1057518872; hg19: chr6-121768433;