17-40363527-T-C

Variant names:

• chr17-40363527-T-C
• rs201734530
• NM_152219.4:c.289A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152219.4(GJD3):​c.289A>G​(p.Met97Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,411,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M97L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GJD3 NM_152219.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 0 publications found

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)

ACMG classification

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=0.15108362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD3	NM_152219.4	c.289A>G	p.Met97Val	missense_variant	Exon 1 of 1	ENST00000578689.2	NP_689343.3
GJD3-AS1	NR_186704.1	n.683T>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	c.289A>G	p.Met97Val	missense_variant	Exon 1 of 1	6	NM_152219.4	ENSP00000463752.1
GJD3-AS1	ENST00000578774.1	n.928T>C		non_coding_transcript_exon_variant	Exon 2 of 2	4
GJD3-AS1	ENST00000791155.1	n.-43T>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1411416 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 697516

African (AFR) AF: 0.00 AC: 0 AN: 32158

American (AMR) AF: 0.00 AC: 0 AN: 36994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 36662

South Asian (SAS) AF: 0.00 AC: 0 AN: 80148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48628

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087236

Other (OTH) AF: 0.00 AC: 0 AN: 58580

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.20	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.53	N
PhyloP100		0.37
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.31		Loss of catalytic residue at V93 (P = 0.0708);
MVP		0.35
MPC		1.3
ClinPred		0.087	T
GERP RS		-0.83
Varity_R		0.091
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201734530; hg19: chr17-38519779;