17-40363293-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_152219.4(GJD3):c.523C>T(p.His175Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,408,200 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.015 ( 29 hom., cov: 32)

Exomes 𝑓: 0.021 ( 320 hom. )

Consequence

GJD3
NM_152219.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.471

Variant links:

Genes affected

GJD3 (HGNC:19147): (gap junction protein delta 3) This gene is a member of the large family of connexins that are required for the formation of gap junctions. Six connexin monomers form a hemichannel, or connexon, on the cell surface. This connexon can interact with a connexon from a neighboring cell, thus forming a channel linking the cytoplasm of the 2 cells. [provided by RefSeq, Jul 2008]

GJD3 links:

GJD3-AS1 (HGNC:56092): (GJD3 antisense RNA 1)

GJD3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073759854).

BP6

Variant 17-40363293-G-A is Benign according to our data. Variant chr17-40363293-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3387758.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0151 (2278/151282) while in subpopulation NFE AF= 0.0228 (1543/67678). AF 95% confidence interval is 0.0219. There are 29 homozygotes in gnomad4. There are 1125 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD3	NM_152219.4 link	c.523C>T	p.His175Tyr	missense_variant	Exon 1 of 1	ENST00000578689.2	NP_689343.3	Q8N144-1A0A654IC68
GJD3-AS1	NR_186704.1 link	n.449G>A		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJD3	ENST00000578689.2 link	c.523C>T	p.His175Tyr	missense_variant	Exon 1 of 1	6	NM_152219.4	ENSP00000463752.1		Q8N144-1
GJD3-AS1	ENST00000578774.1 link	n.694G>A		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2279

AN:

151174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.00492

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0159

GnomAD3 exomes

AF:

0.0135

AC:

784

AN:

57928

Hom.:

AF XY:

0.0130

AC XY:

446

AN XY:

34336

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.00705

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00467

Gnomad FIN exome

AF:

0.0244

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0213

AC:

26827

AN:

1256918

Hom.:

320

Cov.:

AF XY:

0.0211

AC XY:

13008

AN XY:

617164

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.00918

Gnomad4 ASJ exome

AF:

0.00583

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00589

Gnomad4 FIN exome

AF:

0.0211

Gnomad4 NFE exome

AF:

0.0242

Gnomad4 OTH exome

AF:

0.0188

GnomAD4 genome

AF:

0.0151

AC:

2278

AN:

151282

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1125

AN XY:

73948

show subpopulations

Gnomad4 AFR

AF:

0.00357

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.00492

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0227

Gnomad4 NFE

AF:

0.0228

Gnomad4 OTH

AF:

0.0157

Alfa

AF:

0.0191

Hom.:

Bravo

AF:

0.0138

ExAC

AF:

0.00387

AC:

222

Asia WGS

AF:

0.00176

AC:

AN:

3428

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Meniere disease

Benign:1

Jan 09, 2024

Meniere Disease Neuroscience Research Program, Faculty of Medicine and Health, Kolling Institute, The University of Sydney

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The NC_000017.11:g.40363293G>A, is a missense variant in GJD3 gene which produces an amino acid change from a positively charged histidine to a bulky and hydrophobic tyrosine in the extracellular extreme of the connexon. This replacement would produce the loss of the electrostatic interactions that occur between histidine 175 and aspartic 178 in each of the six connexins conforming the homomeric connexon, altering the correct arrangement between two connexons to form the channel. The variant is part of an haplotype involved in Meniere’s Disease, composed by g.40356228C>T, g.40363058C>G, g.40363293G>A, g.40363294C>G and g.40363579G>T. The haplotype was found in 10 individuals with familial Meniere’s Disease, segregating in 3 of these families (PP1); and in another 8 individuals with sporadic Meniere’s Disease. GnomAD exomes allele frequency = 0.0213 is greater than 0.0001 (BS1); however, the frequency of the haplotype for the Iberian population in Spain is 0.0093. The variant was observed in healthy adults in gnomAD (BS2). The MetaRNN value of the variant is 0.00738 (BP4). In summary, this variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied: PP1,BS1,BS2,BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0074

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

0.96

PrimateAI

Pathogenic

0.85

Sift4G

Benign

0.38

Polyphen

0.16

Vest4

0.18

MPC

1.5

ClinPred

0.014

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over