12-29445388-C-T

Position:

• chr12-29445388-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001353179.2(OVCH1):​c.2876G>A​(p.Arg959Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OVCH1 NM_001353179.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0940

Genes affected

OVCH1 (HGNC:23080): (ovochymase 1) Predicted to enable metal ion binding activity and serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be located in extracellular region. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

OVCH1-AS1 (HGNC:44484): (OVCH1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OVCH1	NM_001353179.2	c.2876G>A	p.Arg959Lys	missense_variant	23/26	ENST00000537054.2
OVCH1-AS1	NR_073172.1	n.561-41498C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OVCH1	ENST00000537054.2	c.2876G>A	p.Arg959Lys	missense_variant	23/26	3	NM_001353179.2	P1
OVCH1-AS1	ENST00000551108.2	n.561-41498C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457164 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724894

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

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

Dec 16, 2022

The c.2771G>A (p.R924K) alteration is located in exon 23 (coding exon 23) of the OVCH1 gene. This alteration results from a G to A substitution at nucleotide position 2771, causing the arginine (R) at amino acid position 924 to be replaced by a lysine (K). 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
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.8
DANN	Benign	0.78
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.058
Sift	Benign	0.56	T
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MutPred		0.42		Gain of methylation at R924 (P = 0.029);
MVP		0.44
MPC		0.035
ClinPred		0.11	T
GERP RS		1.4
gMVP		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1941585363; hg19: chr12-29598321;