chr12-109073519-A-T

Variant names:

• chr12-109073519-A-T
• rs1379253469
• NM_032663.5:c.707A>T

Variant summary

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

The NM_032663.5(USP30):​c.707A>T​(p.His236Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,172 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USP30 NM_032663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.17
• 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]

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=0.40283567).

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.707A>T	p.His236Leu	missense	Exon 7 of 13	NP_116052.2	Q70CQ3
	USP30	NM_001301175.2		c.614A>T	p.His205Leu	missense	Exon 10 of 16	NP_001288104.1	B3KUS5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP30	ENST00000257548.10	TSL:1 MANE Select	c.707A>T	p.His236Leu	missense	Exon 7 of 13	ENSP00000257548.5	Q70CQ3
	USP30	ENST00000928066.1		c.707A>T	p.His236Leu	missense	Exon 7 of 13	ENSP00000598125.1
	USP30	ENST00000962121.1		c.707A>T	p.His236Leu	missense	Exon 7 of 13	ENSP00000632180.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460172 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726602

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110470

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 33

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	0.12
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.36
Sift	Benign	0.13	T
Sift4G	Benign	0.29	T
Polyphen		0.18	B
Vest4		0.49
MutPred		0.45		Gain of catalytic residue at M232 (P = 0.0062)
MVP		0.72
MPC		1.2
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.44
Mutation Taster		=49/51	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

Other links and lift over

dbSNP: rs1379253469; hg19: chr12-109511324;