Genetic Variant GJD3:p.His211Arg (chr17-40363184-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152219.4(GJD3):c.632A>G(p.His211Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,444,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

GJD3
NM_152219.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11863577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD3	NM_152219.4 link	c.632A>G	p.His211Arg	missense_variant	Exon 1 of 1	ENST00000578689.2	NP_689343.3	Q8N144-1A0A654IC68
GJD3-AS1	NR_186704.1 link	n.340T>C		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.632A>G	p.His211Arg	missense_variant	Exon 1 of 1	6	NM_152219.4	ENSP00000463752.1		Q8N144-1
GJD3-AS1	ENST00000578774.1 link	n.585T>C		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

AF:

7.73e-7

AC:

AN:

1293336

Hom.:

Cov.:

AF XY:

0.00000157

AC XY:

AN XY:

637618

show subpopulations

Gnomad4 AFR exome

AF:

0.0000375

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151002

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73746

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000278

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632A>G (p.H211R) alteration is located in exon 1 (coding exon 1) of the GJD3 gene. This alteration results from a A to G substitution at nucleotide position 632, causing the histidine (H) at amino acid position 211 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.94

Eigen

Benign

-0.0060

Eigen_PC

Benign

0.047

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.8

Sift4G

Benign

0.13

Polyphen

0.059

Vest4

0.45

MutPred

0.74

Gain of MoRF binding (P = 0.0075);

MVP

0.69

MPC

1.5

ClinPred

0.62

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.27

gMVP

0.64

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