rs1048603

Variant names:

• chr2-233485841-G-A
• rs1048603
• NM_001365479.2:c.3334C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-233485841-G-A
• chr2-233485841-G-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1112H) has been classified as Uncertain significance.

• 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
• Publications: 38 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
USP40	NM_001365479.2	c.3334C>T	p.Arg1112Cys	missense_variant	Exon 29 of 32	ENST00000678225.2	NP_001352408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP40	ENST00000678225.2	c.3334C>T	p.Arg1112Cys	missense_variant	Exon 29 of 32		NM_001365479.2	ENSP00000502952.1

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

GnomAD2 exomes AF: 0.317 AC: 77059 AN: 242714 AF XY: 0.317

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 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

African (AFR) AF: 0.696 AC: 23171 AN: 33314

American (AMR) AF: 0.230 AC: 10116 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9477 AN: 26026

East Asian (EAS) AF: 0.156 AC: 6193 AN: 39606

South Asian (SAS) AF: 0.289 AC: 24609 AN: 85234

European-Finnish (FIN) AF: 0.386 AC: 20499 AN: 53170

Middle Eastern (MID) AF: 0.323 AC: 1860 AN: 5758

European-Non Finnish (NFE) AF: 0.310 AC: 343821 AN: 1110270

Other (OTH) AF: 0.335 AC: 20182 AN: 60230

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

African (AFR) AF: 0.685 AC: 28386 AN: 41414

American (AMR) AF: 0.310 AC: 4737 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1242 AN: 3472

East Asian (EAS) AF: 0.168 AC: 868 AN: 5172

South Asian (SAS) AF: 0.279 AC: 1348 AN: 4824

European-Finnish (FIN) AF: 0.401 AC: 4236 AN: 10566

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21281 AN: 67952

Other (OTH) AF: 0.378 AC: 796 AN: 2108

Alfa AF: 0.329 Hom.: 29764

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
DEOGEN2	Benign	0.00044	.;T;T
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
MutationAssessor	Benign	-0.90	.;N;N
PhyloP100		0.29
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
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: rs1048603; hg19: chr2-234394487; COSMIC: COSV52485896; COSMIC: COSV52485896;