17-40363280-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152219.4(GJD3):​c.536G>T​(p.Cys179Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000786 in 1,271,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

GJD3
NM_152219.4 missense

Scores

10
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.16
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-AS1 (HGNC:56092): (GJD3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJD3NM_152219.4 linkc.536G>T p.Cys179Phe missense_variant Exon 1 of 1 ENST00000578689.2 NP_689343.3 Q8N144-1A0A654IC68
GJD3-AS1NR_186704.1 linkn.436C>A non_coding_transcript_exon_variant Exon 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJD3ENST00000578689.2 linkc.536G>T p.Cys179Phe missense_variant Exon 1 of 1 6 NM_152219.4 ENSP00000463752.1 Q8N144-1
GJD3-AS1ENST00000578774.1 linkn.681C>A non_coding_transcript_exon_variant Exon 2 of 2 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.86e-7
AC:
1
AN:
1271864
Hom.:
0
Cov.:
33
AF XY:
0.00000160
AC XY:
1
AN XY:
625836
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000148
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.536G>T (p.C179F) alteration is located in exon 1 (coding exon 1) of the GJD3 gene. This alteration results from a G to T substitution at nucleotide position 536, causing the cysteine (C) at amino acid position 179 to be replaced by a phenylalanine (F). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.90
Gain of catalytic residue at C179 (P = 0.0112);
MVP
0.73
MPC
3.1
ClinPred
1.0
D
GERP RS
3.4
Varity_R
0.76
gMVP
0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38519532; API