17-40363380-C-G

Variant names:

• chr17-40363380-C-G
• NM_152219.4:c.436G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152219.4(GJD3):​c.436G>C​(p.Ala146Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GJD3 NM_152219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.233

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

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, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD3	NM_152219.4	c.436G>C	p.Ala146Pro	missense_variant	Exon 1 of 1	ENST00000578689.2	NP_689343.3
GJD3-AS1	NR_186704.1	n.536C>G		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.436G>C	p.Ala146Pro	missense_variant	Exon 1 of 1	6	NM_152219.4	ENSP00000463752.1
GJD3-AS1	ENST00000578774.1	n.781C>G		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1245680 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 612158

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: 0.00

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

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.436G>C (p.A146P) alteration is located in exon 1 (coding exon 1) of the GJD3 gene. This alteration results from a G to C substitution at nucleotide position 436, causing the alanine (A) at amino acid position 146 to be replaced by a proline (P). 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	0.86
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	0.077
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.93	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.79		Loss of MoRF binding (P = 0.079);
MVP		0.53
MPC		2.8
ClinPred		0.88	D
GERP RS		3.0
Varity_R		0.55
gMVP		0.70

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: chr17-38519632;