10-35607922-C-T

Position:

• chr10-35607922-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153368.3(GJD4):​c.409C>T​(p.Pro137Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,452,288 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GJD4 NM_153368.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

Genes affected

GJD4 (HGNC:23296): (gap junction protein delta 4) Connexins, such as GJD4, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

ENSG00000273312 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJD4	NM_153368.3	c.409C>T	p.Pro137Ser	missense_variant	2/2	ENST00000321660.2	NP_699199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJD4	ENST00000321660.2	c.409C>T	p.Pro137Ser	missense_variant	2/2	1	NM_153368.3	ENSP00000315070.1
ENSG00000273312	ENST00000609313.1	n.232G>A		non_coding_transcript_exon_variant	1/1	6
ENSG00000273312	ENST00000635993.1	n.101G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452288 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722778

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: 9.01e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2024

The c.409C>T (p.P137S) alteration is located in exon 2 (coding exon 2) of the GJD4 gene. This alteration results from a C to T substitution at nucleotide position 409, causing the proline (P) at amino acid position 137 to be replaced by a serine (S). 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.021
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.34
Sift	Benign	0.034	D
Sift4G	Benign	0.074	T
Polyphen		0.98	D
Vest4		0.53
MutPred		0.48		Loss of stability (P = 0.1322);
MVP		0.67
MPC		0.94
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.51

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: chr10-35896850;