6-121447373-A-G

Variant names:

• chr6-121447373-A-G
• rs878853696
• NM_000165.5:c.526A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000165.5(GJA1):​c.526A>G​(p.Ile176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I176M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.46
• Publications: 0 publications found

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]

GJA1 Gene-Disease associations (from GenCC):

• hypoplastic left heart syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• oculodentodigital dysplasia

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant palmoplantar keratoderma and congenital alopecia

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P
• erythrokeratodermia variabilis et progressiva 3

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• oculodentodigital dysplasia, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• craniometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 3

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• craniometaphyseal dysplasia, autosomal recessive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Hallermann-Streiff syndrome

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a disulfide_bond (size 138) in uniprot entity CXA1_HUMAN there are 23 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, erythrokeratodermia variabilis et progressiva 3, oculodentodigital dysplasia, autosomal dominant palmoplantar keratoderma and congenital alopecia, hypoplastic left heart syndrome 1, craniometaphyseal dysplasia, syndactyly type 3, oculodentodigital dysplasia, autosomal recessive, nonsyndromic genetic hearing loss, Hallermann-Streiff syndrome, erythrokeratodermia variabilis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37893412).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000165.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA1	NM_000165.5	MANE Select	c.526A>G	p.Ile176Val	missense	Exon 2 of 2	NP_000156.1	P17302

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA1	ENST00000282561.4	TSL:1 MANE Select	c.526A>G	p.Ile176Val	missense	Exon 2 of 2	ENSP00000282561.3	P17302
	GJA1	ENST00000647564.1		c.526A>G	p.Ile176Val	missense	Exon 2 of 2	ENSP00000497565.1	P17302
	GJA1	ENST00000649003.1		c.526A>G	p.Ile176Val	missense	Exon 2 of 2	ENSP00000497283.1	P17302

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Oculodentodigital dysplasia, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0060	B
Vest4		0.12
MutPred		0.56		Loss of catalytic residue at L181 (P = 0.0424)
MVP		0.80
MPC		0.41
ClinPred		0.35	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.78
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs878853696; hg19: chr6-121768519;