12-109052752-C-A

Variant names:

• chr12-109052752-C-A
• rs370678568
• NM_032663.5:c.74C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032663.5(USP30):​c.74C>A​(p.Ala25Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,454,246 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: USP30 NM_032663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.514
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105688184).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.74C>A	p.Ala25Glu	missense	Exon 1 of 13	NP_116052.2	Q70CQ3
	USP30	NM_001301175.2		c.-10-3930C>A		intron	N/A	NP_001288104.1	B3KUS5
	USP30-AS1	NR_038996.1		n.281-14G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP30	ENST00000257548.10	TSL:1 MANE Select	c.74C>A	p.Ala25Glu	missense	Exon 1 of 13	ENSP00000257548.5	Q70CQ3
	USP30	ENST00000928066.1		c.74C>A	p.Ala25Glu	missense	Exon 1 of 13	ENSP00000598125.1
	USP30	ENST00000962121.1		c.74C>A	p.Ala25Glu	missense	Exon 1 of 13	ENSP00000632180.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000118 AC: 13 AN: 109762 AF XY: 0.000143

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: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000154 AC: 200 AN: 1302046 Hom.: 2 Cov.: 32 AF XY: 0.000142 AC XY: 91 AN XY: 639500

African (AFR) AF: 0.000961 AC: 25 AN: 26018

American (AMR) AF: 0.000184 AC: 4 AN: 21700

Ashkenazi Jewish (ASJ) AF: 0.000687 AC: 13 AN: 18914

East Asian (EAS) AF: 0.00 AC: 0 AN: 31328

South Asian (SAS) AF: 0.0000308 AC: 2 AN: 64862

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45530

Middle Eastern (MID) AF: 0.00265 AC: 13 AN: 4908

European-Non Finnish (NFE) AF: 0.000118 AC: 122 AN: 1036092

Other (OTH) AF: 0.000380 AC: 20 AN: 52694

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74346

African (AFR) AF: 0.000121 AC: 5 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000146 AC: 1

ExAC AF: 0.000129 AC: 15

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	0.24
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.51
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.21
Sift	Benign	0.17	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.18
MPC		0.47
ClinPred		0.052	T
GERP RS		3.9
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.082
gMVP		0.74
Mutation Taster		=83/17	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: rs370678568; hg19: chr12-109490557;