Genetic Variant GJD3:p.Glu275Lys (chr17-40362993-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152219.4(GJD3):c.823G>A(p.Glu275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GJD3
NM_152219.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.441

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.123900235).

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.823G>A	p.Glu275Lys	missense	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.149C>T		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.823G>A	p.Glu275Lys	missense	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.484-90C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151360

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1068784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

509898

African (AFR)

AF:

0.00

AC:

AN:

21642

American (AMR)

AF:

0.00

AC:

AN:

7768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13024

East Asian (EAS)

AF:

0.00

AC:

AN:

23402

South Asian (SAS)

AF:

0.00

AC:

AN:

25088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2918

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

912412

Other (OTH)

AF:

0.00

AC:

AN:

41626

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151360

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73918

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41334

American (AMR)

AF:

0.0000659

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67794

Other (OTH)

AF:

0.00

AC:

AN:

2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.065

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.56

M_CAP

Benign

0.066

MetaRNN

Benign

0.12

MutationAssessor

Benign

0.69

PhyloP100

0.44

PrimateAI

Pathogenic

0.84

Sift4G

Benign

0.46

Polyphen

0.066

Vest4

0.22

MVP

0.88

MPC

1.5

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.068

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over