rs1048603

chr2-233485841-G-Achr2-233485841-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001365479.2(USP40):c.3334C>T(p.Arg1112Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,609,624 control chromosomes in the GnomAD database, including 91,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (15376 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76070 hom.)
• Consequence: USP40 NM_001365479.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.288

Genes affected

USP40 (HGNC:20069): (ubiquitin specific peptidase 40) Modification of cellular proteins by ubiquitin is an essential regulatory mechanism controlled by the coordinated action of multiple ubiquitin-conjugating and deubiquitinating enzymes. USP40 belongs to a large family of cysteine proteases that function as deubiquitinating enzymes (Quesada et al., 2004 [PubMed 14715245]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1801902E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP40	NM_001365479.2	c.3334C>T	p.Arg1112Cys	missense_variant	29/32	ENST00000678225.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP40	ENST00000678225.2	c.3334C>T	p.Arg1112Cys	missense_variant	29/32		NM_001365479.2	P3

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63211 AN: 151884 Hom.: 15358 Cov.: 32

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.317 AC: 77059 AN: 242714 Hom.: 13814 AF XY: 0.317 AC XY: 41702 AN XY: 131556

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.316 AC: 459928 AN: 1457622 Hom.: 76070 Cov.: 41 AF XY: 0.315 AC XY: 228289 AN XY: 724680

Gnomad4 AFR exome AF: 0.696

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.335

GnomAD4 genome AF: 0.416 AC: 63271 AN: 152002 Hom.: 15376 Cov.: 32 AF XY: 0.413 AC XY: 30696 AN XY: 74308

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.378

Alfa AF: 0.320 Hom.: 20211

Bravo AF: 0.416

TwinsUK AF: 0.305 AC: 1130

ALSPAC AF: 0.300 AC: 1158

ESP6500AA AF: 0.651 AC: 2480

ESP6500EA AF: 0.315 AC: 2595

ExAC AF: 0.321 AC: 38778

Asia WGS AF: 0.270 AC: 941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	10
Dann	Benign	0.94
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.13	T;.;T
MetaRNN	Benign	0.0000022	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.71	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.15
MPC		0.047
ClinPred		0.0088	T
GERP RS		-2.4
Varity_R		0.059
gMVP		0.30

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: rs1048603; hg19: chr2-234394487; COSMIC: COSV52485896; COSMIC: COSV52485896;