NM_152219.4:c.398G>C

Variant names:

• chr17-40363418-C-G
• rs1475862971
• NM_152219.4:c.398G>C

Variant summary

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

The NM_152219.4(GJD3):​c.398G>C​(p.Arg133Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000518 in 1,159,162 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R133L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: GJD3 NM_152219.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.398G>C	p.Arg133Pro	missense	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.574C>G		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.398G>C	p.Arg133Pro	missense	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.819C>G		non_coding_transcript_exon	Exon 2 of 2
	GJD3-AS1	ENST00000791155.1		n.-152C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000518 AC: 6 AN: 1159162 Hom.: 0 Cov.: 33 AF XY: 0.00000712 AC XY: 4 AN XY: 561996

African (AFR) AF: 0.0000432 AC: 1 AN: 23142

American (AMR) AF: 0.00 AC: 0 AN: 8840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15212

East Asian (EAS) AF: 0.00 AC: 0 AN: 26718

South Asian (SAS) AF: 0.00 AC: 0 AN: 39142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3504

European-Non Finnish (NFE) AF: 0.00000517 AC: 5 AN: 967158

Other (OTH) AF: 0.00 AC: 0 AN: 46680

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.55	N
PhyloP100		0.13
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.66		Loss of methylation at R133 (P = 0.0145)
MVP		0.54
MPC		2.9
ClinPred		0.92	D
GERP RS		2.1
Varity_R		0.37
gMVP		0.69
Mutation Taster		=59/41	polymorphism

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: rs1475862971; hg19: chr17-38519670;