2-233485819-T-A

Position:

• chr2-233485819-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365479.2(USP40):​c.3356A>T​(p.Glu1119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP40 NM_001365479.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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]

USP40 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP40	NM_001365479.2	c.3356A>T	p.Glu1119Val	missense_variant	29/32	ENST00000678225.2	NP_001352408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP40	ENST00000678225.2	c.3356A>T	p.Glu1119Val	missense_variant	29/32		NM_001365479.2	ENSP00000502952.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2024

The c.3389A>T (p.E1130V) alteration is located in exon 27 (coding exon 27) of the USP40 gene. This alteration results from a A to T substitution at nucleotide position 3389, causing the glutamic acid (E) at amino acid position 1130 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.9	.;M;M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.96	D;.;.
Vest4		0.68
MutPred		0.40		Gain of sheet (P = 0.0125);.;.;
MVP		0.35
MPC		0.056
ClinPred		0.90	D
GERP RS		4.6
Varity_R		0.15
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-234394465;