17-40363058-C-A

Variant names:

• chr17-40363058-C-A
• rs532965992
• NM_152219.4:c.758G>T

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.758G>T​(p.Arg253Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,080,906 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. 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. R253P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GJD3 NM_152219.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.51
• 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=0.08541635).

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.758G>T	p.Arg253Leu	missense	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.214C>A		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.758G>T	p.Arg253Leu	missense	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.484-25C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000278 AC: 3 AN: 1080906 Hom.: 0 Cov.: 33 AF XY: 0.00000195 AC XY: 1 AN XY: 513126

African (AFR) AF: 0.00 AC: 0 AN: 22466

American (AMR) AF: 0.00 AC: 0 AN: 8030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13876

East Asian (EAS) AF: 0.00 AC: 0 AN: 25952

South Asian (SAS) AF: 0.00 AC: 0 AN: 22958

European-Finnish (FIN) AF: 0.000140 AC: 3 AN: 21386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920010

Other (OTH) AF: 0.00 AC: 0 AN: 43112

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	5.6
DANN	Benign	0.86
DEOGEN2	Benign	0.074	T
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.085	T
MutationAssessor	Benign	0.34	N
PhyloP100		-5.5
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.47	T
Polyphen		0.0090	B
Vest4		0.10
MVP		0.80
MPC		1.6
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.086
gMVP		0.23

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

Other links and lift over

dbSNP: rs532965992; hg19: chr17-38519310;