rs373785473

Variant names:

• chr12-6855525-C-T
• rs373785473
• NM_001098536.2:c.236C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001098536.2(USP5):​c.236C>T​(p.Pro79Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: USP5 NM_001098536.2 missense, splice_region
• Scores: Splicing: ADA: 0.0007733
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.492

Genes affected

USP5 (HGNC:12628): (ubiquitin specific peptidase 5) Ubiquitin (see MIM 191339)-dependent proteolysis is a complex pathway of protein metabolism implicated in such diverse cellular functions as maintenance of chromatin structure, receptor function, and degradation of abnormal proteins. A late step of the process involves disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. USP5 disassembles branched polyubiquitin chains by a sequential exo mechanism, starting at the proximal end of the chain (Wilkinson et al., 1995 [PubMed 7578059]).[supplied by OMIM, Mar 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032649457).
• BP6: Variant 12-6855525-C-T is Benign according to our data. Variant chr12-6855525-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2407082.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP5	NM_001098536.2	c.236C>T	p.Pro79Leu	missense_variant, splice_region_variant	Exon 2 of 20	ENST00000229268.13	NP_001092006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP5	ENST00000229268.13	c.236C>T	p.Pro79Leu	missense_variant, splice_region_variant	Exon 2 of 20	1	NM_001098536.2	ENSP00000229268.8
USP5	ENST00000389231.9	c.236C>T	p.Pro79Leu	missense_variant, splice_region_variant	Exon 2 of 20	1		ENSP00000373883.5
USP5	ENST00000542087.1	c.236C>T	p.Pro79Leu	missense_variant, splice_region_variant	Exon 2 of 5	3		ENSP00000444668.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000638 AC: 16 AN: 250836 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000246 AC: 11 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 30, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N;N;.
PhyloP100		-0.49
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.11	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.21
MVP		0.13
MPC		0.72
ClinPred		0.0083	T
GERP RS		2.0
Varity_R		0.027
gMVP		0.40
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00077
dbscSNV1_RF	Benign	0.072
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: rs373785473; hg19: chr12-6964689;