12-6863250-C-T

Variant names:

• chr12-6863250-C-T
• rs35165406
• NM_001098536.2:c.1827C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001098536.2(USP5):​c.1827C>T​(p.Pro609Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,614,114 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (139 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (110 hom.)
• Consequence: USP5 NM_001098536.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.64
• Publications: 2 publications found

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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-6863250-C-T is Benign according to our data. Variant chr12-6863250-C-T is described in ClinVar as [Benign]. Clinvar id is 781062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP5	NM_001098536.2	c.1827C>T	p.Pro609Pro	synonymous_variant	Exon 15 of 20	ENST00000229268.13	NP_001092006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP5	ENST00000229268.13	c.1827C>T	p.Pro609Pro	synonymous_variant	Exon 15 of 20	1	NM_001098536.2	ENSP00000229268.8

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3382 AN: 152116 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00591 AC: 1485 AN: 251330 AF XY: 0.00449

Gnomad AFR exome AF: 0.0777

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00257 AC: 3755 AN: 1461880 Hom.: 110 Cov.: 31 AF XY: 0.00227 AC XY: 1650 AN XY: 727242

African (AFR) AF: 0.0828 AC: 2772 AN: 33480

American (AMR) AF: 0.00362 AC: 162 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.000533 AC: 46 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.000335 AC: 373 AN: 1112008

Other (OTH) AF: 0.00522 AC: 315 AN: 60392

GnomAD4 genome AF: 0.0223 AC: 3391 AN: 152234 Hom.: 139 Cov.: 32 AF XY: 0.0223 AC XY: 1658 AN XY: 74428

African (AFR) AF: 0.0771 AC: 3200 AN: 41520

American (AMR) AF: 0.00811 AC: 124 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68024

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

Alfa AF: 0.0101 Hom.: 25

Bravo AF: 0.0241

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.29
DANN	Benign	0.82
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs35165406; hg19: chr12-6972414; COSMIC: COSV57539360; COSMIC: COSV57539360;