Variant 6-41798841-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001286554.2(USP49):c.1759A>G(p.Met587Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

USP49
NM_001286554.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

Variant links:

Genes affected

USP49 (HGNC:20078): (ubiquitin specific peptidase 49) Enables cysteine-type endopeptidase activity; histone binding activity; and thiol-dependent deubiquitinase. Involved in histone H2B conserved C-terminal lysine deubiquitination and mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

USP49 links:

ENSG00000288721 (HGNC:):

ENSG00000288721 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05386871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP49	NM_001286554.2 linkuse as main transcript	c.1759A>G	p.Met587Val	missense_variant	7/8	ENST00000682992.1	NP_001273483.1	Q70CQ1-1
USP49	NM_001384542.1 linkuse as main transcript	c.1759A>G	p.Met587Val	missense_variant	7/8		NP_001371471.1
USP49	NM_018561.5 linkuse as main transcript	c.1759A>G	p.Met587Val	missense_variant	7/7		NP_061031.2	Q70CQ1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USP49	ENST00000682992.1 linkuse as main transcript	c.1759A>G	p.Met587Val	missense_variant	7/8		NM_001286554.2	ENSP00000507239.1	Q70CQ1-1
USP49	ENST00000373010.5 linkuse as main transcript	c.1725+34A>G		intron_variant		5		ENSP00000362101.1	Q5T3E1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*1917A>G		non_coding_transcript_exon_variant	9/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*1917A>G		3_prime_UTR_variant	9/10			ENSP00000507261.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

8.99e-7

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

Mar 07, 2023

The c.1759A>G (p.M587V) alteration is located in exon 7 (coding exon 4) of the USP49 gene. This alteration results from a A to G substitution at nucleotide position 1759, causing the methionine (M) at amino acid position 587 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

0.060

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.75

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.065

Sift

Benign

0.53

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0

.;B

Vest4

0.27

MutPred

0.45

Loss of disorder (P = 0.1419);Loss of disorder (P = 0.1419);

MVP

0.093

MPC

0.76

ClinPred

0.57

GERP RS

6.2

Varity_R

0.060

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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