12-109052734-G-C

Variant names:

• chr12-109052734-G-C
• rs1227161734
• NM_032663.5:c.56G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032663.5(USP30):​c.56G>C​(p.Arg19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,312,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: USP30 NM_032663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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]

USP30-AS1 (HGNC:40909): (USP30 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19470617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP30	NM_032663.5	c.56G>C	p.Arg19Pro	missense_variant	Exon 1 of 13	ENST00000257548.10	NP_116052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP30	ENST00000257548.10	c.56G>C	p.Arg19Pro	missense_variant	Exon 1 of 13	1	NM_032663.5	ENSP00000257548.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1312826 Hom.: 0 Cov.: 32 AF XY: 0.00000155 AC XY: 1 AN XY: 645750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000317

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.60e-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

Oct 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56G>C (p.R19P) alteration is located in exon 1 (coding exon 1) of the USP30 gene. This alteration results from a G to C substitution at nucleotide position 56, causing the arginine (R) at amino acid position 19 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.22
Sift	Benign	0.10	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0010	B;.
Vest4		0.32
MutPred		0.49		Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);
MVP		0.39
MPC		0.88
ClinPred		0.62	D
GERP RS		3.9
Varity_R		0.26
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs1227161734; hg19: chr12-109490539;