Variant 2-233477478-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001365479.2(USP40):c.3625A>T(p.Ser1209Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USP40
NM_001365479.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.654

Variant links:

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 links:

USP40 (HGNC:):

USP40 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08953783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP40	NM_001365479.2 linkuse as main transcript	c.3625A>T	p.Ser1209Cys	missense_variant	32/32	ENST00000678225.2	NP_001352408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USP40	ENST00000678225.2 linkuse as main transcript	c.3625A>T	p.Ser1209Cys	missense_variant	32/32		NM_001365479.2	ENSP00000502952.1	A0A7I2YQ75
USP40	ENST00000427112.6 linkuse as main transcript	c.3622A>T	p.Ser1208Cys	missense_variant	31/31	1		ENSP00000387898.2	Q9NVE5-1
USP40	ENST00000483519.5 linkuse as main transcript	n.770A>T		non_coding_transcript_exon_variant	6/6	1
USP40	ENST00000251722.10 linkuse as main transcript	c.3622A>T	p.Ser1208Cys	missense_variant	32/32	5		ENSP00000251722.6	Q9NVE5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461350

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726922

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The c.3658A>T (p.S1220C) alteration is located in exon 30 (coding exon 30) of the USP40 gene. This alteration results from a A to T substitution at nucleotide position 3658, causing the serine (S) at amino acid position 1220 to be replaced by a cysteine (C). 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

0.088

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.0

DANN

Benign

0.95

DEOGEN2

Benign

0.0064

.;T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.37

T;.;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;M;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.088

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.93

P;.;.

Vest4

0.17

MutPred

0.18

Loss of phosphorylation at S1220 (P = 0.0176);.;.;

MVP

0.26

MPC

0.19

ClinPred

0.48

GERP RS

-2.6

Varity_R

0.048

gMVP

0.15

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over