rs397824185

chr6-121447998-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000165.5(GJA1):c.*3dup variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0524 in 1,612,164 control chromosomes in the GnomAD database, including 6,626 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (760 hom., cov: 32)
  • Exomes 𝑓: 0.052 (5866 hom.)
• Consequence: GJA1 NM_000165.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.439

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 6-121447998-T-TA is Benign according to our data. Variant chr6-121447998-T-TA is described in ClinVar as [Benign]. Clinvar id is 255409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA1	NM_000165.5	c.*3dup		3_prime_UTR_variant	2/2	ENST00000282561.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA1	ENST00000282561.4	c.*3dup		3_prime_UTR_variant	2/2	1	NM_000165.5	P1
GJA1	ENST00000647564.1	c.*3dup		3_prime_UTR_variant	2/2			P1
GJA1	ENST00000649003.1	c.*3dup		3_prime_UTR_variant	2/2			P1
GJA1	ENST00000650427.1	c.*3dup		3_prime_UTR_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8579 AN: 152004 Hom.: 761 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0440

Gnomad OTH AF: 0.0622

GnomAD3 exomes AF: 0.0922 AC: 22900 AN: 248330 Hom.: 3991 AF XY: 0.0772 AC XY: 10426 AN XY: 135026

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.00196

Gnomad SAS exome AF: 0.0234

Gnomad FIN exome AF: 0.0414

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0734

GnomAD4 exome AF: 0.0520 AC: 75939 AN: 1460042 Hom.: 5866 Cov.: 30 AF XY: 0.0494 AC XY: 35884 AN XY: 726426

Gnomad4 AFR exome AF: 0.00975

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.0507

Gnomad4 EAS exome AF: 0.00171

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.0409

Gnomad4 NFE exome AF: 0.0433

Gnomad4 OTH exome AF: 0.0499

GnomAD4 genome AF: 0.0564 AC: 8579 AN: 152122 Hom.: 760 Cov.: 32 AF XY: 0.0601 AC XY: 4472 AN XY: 74374

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.0440

Gnomad4 OTH AF: 0.0616

Alfa AF: 0.0322 Hom.: 44

Bravo AF: 0.0754

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.0396

EpiControl AF: 0.0394

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2019	- -

Oculodentodigital dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Syndactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Oculodentodigital dysplasia, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2023

- -

Hypoplastic left heart syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs397824185; hg19: chr6-121769144;