chr12-109073506-A-G

Variant names:

• chr12-109073506-A-G
• rs2041507550
• NM_032663.5:c.694A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032663.5(USP30):​c.694A>G​(p.Met232Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USP30 NM_032663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.49

Genes affected

USP30 (HGNC:20065): (ubiquitin specific peptidase 30) USP30, a member of the ubiquitin-specific protease family (see USP1, MIM 603478), is a novel mitochondrial deubiquitinating (DUB) enzyme (Nakamura and Hirose, 2008 [PubMed 18287522]).[supplied by OMIM, Dec 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41393557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP30	NM_032663.5	c.694A>G	p.Met232Val	missense_variant	Exon 7 of 13	ENST00000257548.10	NP_116052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP30	ENST00000257548.10	c.694A>G	p.Met232Val	missense_variant	Exon 7 of 13	1	NM_032663.5	ENSP00000257548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.694A>G (p.M232V) alteration is located in exon 7 (coding exon 7) of the USP30 gene. This alteration results from a A to G substitution at nucleotide position 694, causing the methionine (M) at amino acid position 232 to be replaced by a valine (V). 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	0.69
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	.;T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.075	.;N
PhyloP100		8.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.013	.;B
Vest4		0.66
MutPred		0.41		.;Gain of catalytic residue at K235 (P = 5e-04);
MVP		0.20
MPC		1.1
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.50
Mutation Taster		=29/71	disease causing

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

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Other links and lift over

dbSNP: rs2041507550; hg19: chr12-109511311;