Genetic Variant GJD3:p.Pro174Pro (chr17-40363294-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_152219.4(GJD3):c.522G>C(p.Pro174Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,404,810 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts 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 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.551

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.2).

BP6

Variant 17-40363294-C-G is Benign according to our data. Variant chr17-40363294-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3387759.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.551 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0151 (2279/151196) while in subpopulation NFE AF = 0.0228 (1543/67646). AF 95% confidence interval is 0.0219. There are 29 homozygotes in GnomAd4. There are 1124 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.522G>C	p.Pro174Pro	synonymous	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.450C>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.522G>C	p.Pro174Pro	synonymous	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.695C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2280

AN:

151088

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:

0.0228

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0228

Gnomad OTH

AF:

0.0159

GnomAD2 exomes

AF:

0.0138

AC:

786

AN:

56988

AF XY:

0.0132

show subpopulations

Gnomad AFR exome

AF:

0.00256

Gnomad AMR exome

AF:

0.00727

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0246

Gnomad NFE exome

AF:

0.0242

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0214

AC:

26830

AN:

1253614

Hom.:

320

Cov.:

AF XY:

0.0211

AC XY:

13007

AN XY:

615266

show subpopulations

African (AFR)

AF:

0.00298

AC:

AN:

25544

American (AMR)

AF:

0.00933

AC:

193

AN:

20678

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

121

AN:

20958

East Asian (EAS)

AF:

0.00

AC:

AN:

27470

South Asian (SAS)

AF:

0.00595

AC:

388

AN:

65260

European-Finnish (FIN)

AF:

0.0211

AC:

659

AN:

31246

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5172

European-Non Finnish (NFE)

AF:

0.0242

AC:

24361

AN:

1006230

Other (OTH)

AF:

0.0189

AC:

964

AN:

51056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1434

2868

4301

5735

7169

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:

2279

AN:

151196

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1124

AN XY:

73888

show subpopulations

African (AFR)

AF:

0.00357

AC:

148

AN:

41452

American (AMR)

AF:

0.0182

AC:

277

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00492

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00539

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0228

AC:

231

AN:

10118

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0228

AC:

1543

AN:

67646

Other (OTH)

AF:

0.0157

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

210

315

420

525

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:

0.00353

Hom.:

Bravo

AF:

0.0138

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

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

-0.55

Mutation Taster

=99/1

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