chr12-109052713-C-T

Variant names:

• chr12-109052713-C-T
• rs372711001
• NM_032663.5:c.35C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032663.5(USP30):​c.35C>T​(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 1,482,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: USP30 NM_032663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.386
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12910151).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032663.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP30	NM_032663.5	MANE Select	c.35C>T	p.Ala12Val	missense	Exon 1 of 13	NP_116052.2	Q70CQ3
	USP30	NM_001301175.2		c.-10-3969C>T		intron	N/A	NP_001288104.1	B3KUS5
	USP30-AS1	NR_038996.1		n.306G>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP30	ENST00000257548.10	TSL:1 MANE Select	c.35C>T	p.Ala12Val	missense	Exon 1 of 13	ENSP00000257548.5	Q70CQ3
	USP30	ENST00000928066.1		c.35C>T	p.Ala12Val	missense	Exon 1 of 13	ENSP00000598125.1
	USP30	ENST00000962121.1		c.35C>T	p.Ala12Val	missense	Exon 1 of 13	ENSP00000632180.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000804 AC: 1 AN: 124418 AF XY: 0.0000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000737

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1330758 Hom.: 0 Cov.: 32 AF XY: 0.00000152 AC XY: 1 AN XY: 656246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26690

American (AMR) AF: 0.00 AC: 0 AN: 25944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20630

East Asian (EAS) AF: 0.0000316 AC: 1 AN: 31628

South Asian (SAS) AF: 0.00 AC: 0 AN: 70810

European-Finnish (FIN) AF: 0.0000221 AC: 1 AN: 45278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050720

Other (OTH) AF: 0.0000185 AC: 1 AN: 54026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.39
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.050
Sift	Uncertain	0.015	D
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.48		Gain of catalytic residue at M10 (P = 0)
MVP		0.18
MPC		0.39
ClinPred		0.29	T
GERP RS		1.5
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.043
gMVP		0.74
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs372711001; hg19: chr12-109490518;