rs11961755

Variant names:

• chr6-121445140-G-A
• rs11961755
• NM_000165.5:c.-16-1692G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000165.5(GJA1):​c.-16-1692G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,094 control chromosomes in the GnomAD database, including 4,113 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4113 hom., cov: 32)
• Consequence: GJA1 NM_000165.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 8 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, SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• oculodentodigital dysplasia, autosomal recessive

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

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• craniometaphyseal dysplasia, autosomal recessive

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA1	NM_000165.5	c.-16-1692G>A		intron_variant	Intron 1 of 1	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.-16-1692G>A		intron_variant	Intron 1 of 1	1	NM_000165.5	ENSP00000282561.3
GJA1	ENST00000647564.1	c.-16-1692G>A		intron_variant	Intron 1 of 1			ENSP00000497565.1
GJA1	ENST00000649003.1	c.-16-1692G>A		intron_variant	Intron 1 of 1			ENSP00000497283.1
GJA1	ENST00000650427.1	c.-16-1692G>A		intron_variant	Intron 1 of 1			ENSP00000497367.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34321 AN: 151976 Hom.: 4110 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.238

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

GnomAD4 genome AF: 0.226 AC: 34340 AN: 152094 Hom.: 4113 Cov.: 32 AF XY: 0.227 AC XY: 16892 AN XY: 74356

African (AFR) AF: 0.196 AC: 8141 AN: 41504

American (AMR) AF: 0.184 AC: 2819 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3470

East Asian (EAS) AF: 0.0261 AC: 135 AN: 5172

South Asian (SAS) AF: 0.216 AC: 1042 AN: 4818

European-Finnish (FIN) AF: 0.296 AC: 3126 AN: 10560

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17705 AN: 67966

Other (OTH) AF: 0.234 AC: 495 AN: 2112

Alfa AF: 0.253 Hom.: 2711

Bravo AF: 0.212

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.85
DANN	Benign	0.67
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs11961755; hg19: chr6-121766286;