21-15831466-A-T

Variant names:

• chr21-15831466-A-T
• rs2297248
• NM_001283041.3:c.1830A>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001283041.3(USP25):​c.1830A>T​(p.Ala610Ala) 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
• Publications: 16 publications found

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]

USP25 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.064).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283041.3. 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
	USP25	NM_001283041.3	MANE Select	c.1830A>T	p.Ala610Ala	synonymous	Exon 16 of 26	NP_001269970.1	Q9UHP3-3
	USP25	NM_001283042.3		c.1830A>T	p.Ala610Ala	synonymous	Exon 16 of 25	NP_001269971.1	Q9UHP3-1
	USP25	NM_013396.6		c.1830A>T	p.Ala610Ala	synonymous	Exon 16 of 24	NP_037528.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP25	ENST00000400183.7	TSL:1 MANE Select	c.1830A>T	p.Ala610Ala	synonymous	Exon 16 of 26	ENSP00000383044.2	Q9UHP3-3
	USP25	ENST00000285681.6	TSL:1	c.1830A>T	p.Ala610Ala	synonymous	Exon 16 of 25	ENSP00000285681.2	Q9UHP3-1
	USP25	ENST00000285679.10	TSL:1	c.1830A>T	p.Ala610Ala	synonymous	Exon 16 of 24	ENSP00000285679.6	Q9UHP3-2

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

GnomAD2 exomes AF: 0.0938 AC: 23581 AN: 251322 AF XY: 0.0871

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 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

African (AFR) AF: 0.368 AC: 12312 AN: 33476

American (AMR) AF: 0.111 AC: 4960 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0840 AC: 2195 AN: 26132

East Asian (EAS) AF: 0.145 AC: 5769 AN: 39682

South Asian (SAS) AF: 0.0969 AC: 8357 AN: 86254

European-Finnish (FIN) AF: 0.0368 AC: 1965 AN: 53420

Middle Eastern (MID) AF: 0.114 AC: 659 AN: 5768

European-Non Finnish (NFE) AF: 0.0444 AC: 49344 AN: 1111932

Other (OTH) AF: 0.0830 AC: 5011 AN: 60394

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

African (AFR) AF: 0.348 AC: 14411 AN: 41466

American (AMR) AF: 0.118 AC: 1805 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 284 AN: 3468

East Asian (EAS) AF: 0.179 AC: 927 AN: 5166

South Asian (SAS) AF: 0.104 AC: 500 AN: 4818

European-Finnish (FIN) AF: 0.0369 AC: 391 AN: 10600

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0472 AC: 3211 AN: 67980

Other (OTH) AF: 0.128 AC: 270 AN: 2106

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.0
DANN	Benign	0.74
PhyloP100		-1.2
Mutation Taster		=97/3	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: rs2297248; hg19: chr21-17203785; COSMIC: COSV99583238;