rs397824185

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000165.5(GJA1):c.*3dupA 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

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.439

Publications

2 publications found

Variant links:

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

GJA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GJA1	NM_000165.5 link	c.*3dupA		3_prime_UTR_variant	Exon 2 of 2	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GJA1	ENST00000282561.4 link	c.*3dupA	3_prime_UTR_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3
GJA1	ENST00000647564.1 link	c.*3dupA	3_prime_UTR_variant	Exon 2 of 2			ENSP00000497565.1
GJA1	ENST00000649003.1 link	c.*3dupA	3_prime_UTR_variant	Exon 2 of 2			ENSP00000497283.1
GJA1	ENST00000650427.1 link	c.*3dupA	3_prime_UTR_variant	Exon 2 of 2			ENSP00000497367.1

Frequencies

GnomAD3 genomes

AF:

0.0564

AC:

8579

AN:

152004

Hom.:

761

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0922

AC:

22900

AN:

248330

AF XY:

0.0772

show subpopulations

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 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.:

AF XY:

0.0494

AC XY:

35884

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.00975

AC:

326

AN:

33426

American (AMR)

AF:

0.423

AC:

18916

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0507

AC:

1325

AN:

26122

East Asian (EAS)

AF:

0.00171

AC:

AN:

39694

South Asian (SAS)

AF:

0.0230

AC:

1984

AN:

86220

European-Finnish (FIN)

AF:

0.0409

AC:

2185

AN:

53412

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0433

AC:

48058

AN:

1110378

Other (OTH)

AF:

0.0499

AC:

3012

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

3332

6665

9997

13330

16662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1930

3860

5790

7720

9650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0564

AC:

8579

AN:

152122

Hom.:

760

Cov.:

AF XY:

0.0601

AC XY:

4472

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0136

AC:

563

AN:

41528

American (AMR)

AF:

0.267

AC:

4082

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

171

AN:

3470

East Asian (EAS)

AF:

0.00291

AC:

AN:

5152

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4820

European-Finnish (FIN)

AF:

0.0444

AC:

469

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0440

AC:

2990

AN:

68000

Other (OTH)

AF:

0.0616

AC:

130

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

362

724

1086

1448

1810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0322

Hom.:

Bravo

AF:

0.0754

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0396

EpiControl

AF:

0.0394

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Oct 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oculodentodigital dysplasia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Syndactyly

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculodentodigital dysplasia, autosomal recessive

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypoplastic left heart syndrome 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.44

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over