6-121446897-AC-CT

Variant names:

• chr6-121446897-AC-CT
• NM_000165.5:c.50_51delACinsCT
• GJA1 p.Tyr17Ser

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM1 PP2 PP3

The NM_000165.5(GJA1):​c.50_51delACinsCT​(p.Tyr17Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_000165.5 (GJA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000165.5
• 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 Hallermann-Streiff syndrome, oculodentodigital dysplasia, erythrokeratodermia variabilis et progressiva 3, oculodentodigital dysplasia, autosomal recessive, congenital heart disease, nonsyndromic genetic hearing loss, syndactyly type 3, autosomal dominant palmoplantar keratoderma and congenital alopecia, erythrokeratodermia variabilis, craniometaphyseal dysplasia, autosomal recessive, hypoplastic left heart syndrome 1, craniometaphyseal dysplasia.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.50_51delACinsCT	p.Tyr17Ser	missense	N/A	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.50_51delACinsCT	p.Tyr17Ser	missense	N/A	ENSP00000282561.3	P17302
	GJA1	ENST00000647564.1		c.50_51delACinsCT	p.Tyr17Ser	missense	N/A	ENSP00000497565.1	P17302
	GJA1	ENST00000649003.1		c.50_51delACinsCT	p.Tyr17Ser	missense	N/A	ENSP00000497283.1	P17302

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-121768043;