17-40363235-T-A

Variant names:

• chr17-40363235-T-A
• rs1413872032
• NM_152219.4:c.581A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152219.4(GJD3):​c.581A>T​(p.Tyr194Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000772 in 1,295,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y194C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: GJD3 NM_152219.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.777
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

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.581A>T	p.Tyr194Phe	missense	Exon 1 of 1	NP_689343.3
	GJD3-AS1	NR_186704.1		n.391T>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.581A>T	p.Tyr194Phe	missense	Exon 1 of 1	ENSP00000463752.1	Q8N144-1
	GJD3-AS1	ENST00000578774.1	TSL:4	n.636T>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295614 Hom.: 0 Cov.: 33 AF XY: 0.00000156 AC XY: 1 AN XY: 639022

African (AFR) AF: 0.00 AC: 0 AN: 26894

American (AMR) AF: 0.00 AC: 0 AN: 26790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22746

East Asian (EAS) AF: 0.00 AC: 0 AN: 28092

South Asian (SAS) AF: 0.00 AC: 0 AN: 70090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5384

European-Non Finnish (NFE) AF: 9.71e-7 AC: 1 AN: 1030264

Other (OTH) AF: 0.00 AC: 0 AN: 53280

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.78
Sift4G	Benign	0.79	T
Polyphen		1.0	D
Vest4		0.34
MutPred		0.66		Gain of sheet (P = 0.0125)
MVP		0.58
MPC		2.4
ClinPred		0.96	D
GERP RS		3.4
Varity_R		0.24
gMVP		0.45
Mutation Taster		=86/14	polymorphism

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: rs1413872032; hg19: chr17-38519487;