rs2297248

chr21-15831466-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001283041.3(USP25):c.1830A>T(p.Ala610=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,613,874 control chromosomes in the GnomAD database, including 8,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (2849 hom., cov: 32)
  • Exomes 𝑓: 0.062 (5178 hom.)
• Consequence: USP25 NM_001283041.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19

Genes affected

USP25 (HGNC:12624): (ubiquitin specific peptidase 25) Ubiquitin (MIM 191339) is a highly conserved 76-amino acid protein involved in regulation of intracellular protein breakdown, cell cycle regulation, and stress response. Ubiquitin is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases (USPs), such as USP25 (Valero et al., 1999 [PubMed 10644437]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP25	NM_001283041.3	c.1830A>T	p.Ala610=	synonymous_variant	16/26	ENST00000400183.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP25	ENST00000400183.7	c.1830A>T	p.Ala610=	synonymous_variant	16/26	1	NM_001283041.3	A1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21840 AN: 151972 Hom.: 2830 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.0938 AC: 23581 AN: 251322 Hom.: 2020 AF XY: 0.0871 AC XY: 11830 AN XY: 135828

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0817

GnomAD4 exome AF: 0.0620 AC: 90572 AN: 1461782 Hom.: 5178 Cov.: 32 AF XY: 0.0621 AC XY: 45166 AN XY: 727188

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0840

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.0969

Gnomad4 FIN exome AF: 0.0368

Gnomad4 NFE exome AF: 0.0444

Gnomad4 OTH exome AF: 0.0830

GnomAD4 genome AF: 0.144 AC: 21909 AN: 152092 Hom.: 2849 Cov.: 32 AF XY: 0.143 AC XY: 10597 AN XY: 74344

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0819

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0369

Gnomad4 NFE AF: 0.0472

Gnomad4 OTH AF: 0.128

Alfa AF: 0.0766 Hom.: 282

Bravo AF: 0.159

Asia WGS AF: 0.184 AC: 643 AN: 3478

EpiCase AF: 0.0511

EpiControl AF: 0.0531

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	2.0
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs2297248; hg19: chr21-17203785; COSMIC: COSV99583238;