dbSNP rs202055764: GJD3:p.His175Tyr (chr17-40363293-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -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. 11/19 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

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152219.4. 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
	GJD3	NM_152219.4	MANE Select	c.523C>T	p.His175Tyr	missense	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.449G>A		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJD3	ENST00000578689.2	TSL:6 MANE Select	c.523C>T	p.His175Tyr	missense	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.694G>A		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes

AF:

0.0135

AC:

784

AN:

57928

AF XY:

0.0130

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 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

African (AFR)

AF:

0.00293

AC:

AN:

25586

American (AMR)

AF:

0.00918

AC:

192

AN:

20908

Ashkenazi Jewish (ASJ)

AF:

0.00583

AC:

123

AN:

21096

East Asian (EAS)

AF:

0.00

AC:

AN:

27500

South Asian (SAS)

AF:

0.00589

AC:

389

AN:

66034

European-Finnish (FIN)

AF:

0.0211

AC:

661

AN:

31376

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

0.0242

AC:

24356

AN:

1008008

Other (OTH)

AF:

0.0188

AC:

963

AN:

51200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1441

2881

4322

5762

7203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

994

1988

2982

3976

4970

<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:

0.0151

AC:

2278

AN:

151282

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1125

AN XY:

73948

show subpopulations

African (AFR)

AF:

0.00357

AC:

148

AN:

41478

American (AMR)

AF:

0.0182

AC:

277

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00492

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00539

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0227

AC:

230

AN:

10144

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0228

AC:

1543

AN:

67678

Other (OTH)

AF:

0.0157

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

106

212

319

425

531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0191

Hom.:

Bravo

AF:

0.0138

ExAC

AF:

0.00387

AC:

222

Asia WGS

AF:

0.00176

AC:

AN:

3428

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Meniere disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

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

PhyloP100

0.47

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

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over