Genetic Variant GJD3:p.Arg253Pro (chr17-40363058-C-G) – 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.758G>C(p.Arg253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,231,732 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.015 ( 31 hom., cov: 32)

Exomes 𝑓: 0.022 ( 286 hom. )

Consequence

GJD3
NM_152219.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.51

Publications

6 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=0.004409313).

BP6

Variant 17-40363058-C-G is Benign according to our data. Variant chr17-40363058-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3387757.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0152 (2287/150844) while in subpopulation NFE AF = 0.0228 (1541/67526). AF 95% confidence interval is 0.0219. There are 31 homozygotes in GnomAd4. There are 1133 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 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.758G>C	p.Arg253Pro	missense	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.214C>G		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.758G>C	p.Arg253Pro	missense	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.484-25C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2288

AN:

150734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00407

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.00492

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0226

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0155

GnomAD2 exomes

AF:

0.0321

AC:

AN:

374

AF XY:

0.0229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0316

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0223

AC:

24086

AN:

1080888

Hom.:

286

Cov.:

AF XY:

0.0224

AC XY:

11489

AN XY:

513114

show subpopulations

African (AFR)

AF:

0.00316

AC:

AN:

22466

American (AMR)

AF:

0.0130

AC:

104

AN:

8030

Ashkenazi Jewish (ASJ)

AF:

0.00541

AC:

AN:

13876

East Asian (EAS)

AF:

0.0000385

AC:

AN:

25952

South Asian (SAS)

AF:

0.00549

AC:

126

AN:

22956

European-Finnish (FIN)

AF:

0.0207

AC:

443

AN:

21386

Middle Eastern (MID)

AF:

0.0119

AC:

AN:

3116

European-Non Finnish (NFE)

AF:

0.0243

AC:

22400

AN:

919994

Other (OTH)

AF:

0.0192

AC:

829

AN:

43112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1287

2574

3862

5149

6436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

990

1980

2970

3960

4950

<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:

0.0152

AC:

2287

AN:

150844

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1133

AN XY:

73716

show subpopulations

African (AFR)

AF:

0.00406

AC:

168

AN:

41404

American (AMR)

AF:

0.0180

AC:

273

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00492

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00539

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0226

AC:

226

AN:

10012

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0228

AC:

1541

AN:

67526

Other (OTH)

AF:

0.0153

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

125

250

376

501

626

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:

0.0164

Hom.:

Bravo

AF:

0.0139

ExAC

AF:

0.00298

AC:

Asia WGS

AF:

0.00233

AC:

AN:

3442

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

0.052

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

6.2

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.062

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0044

MutationAssessor

Benign

0.34

PhyloP100

-5.5

PrimateAI

Uncertain

0.79

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.092

MPC

1.7

GERP RS

-1.6

Varity_R

0.14

gMVP

0.19

Mutation Taster

=84/16

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

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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