Genetic Variant USP49:p.Gly334Ser (chr6-41805984-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001286554.2(USP49):c.1000G>A(p.Gly334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

USP49
NM_001286554.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.98

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=0.12179139).

BP6

Variant 6-41805984-C-T is Benign according to our data. Variant chr6-41805984-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3814403.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP49	NM_001286554.2 link	c.1000G>A	p.Gly334Ser	missense_variant	Exon 4 of 8	ENST00000682992.1	NP_001273483.1	Q70CQ1-1
USP49	NM_001384542.1 link	c.1000G>A	p.Gly334Ser	missense_variant	Exon 4 of 8		NP_001371471.1
USP49	NM_018561.5 link	c.1000G>A	p.Gly334Ser	missense_variant	Exon 4 of 7		NP_061031.2	Q70CQ1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP49	ENST00000682992.1 link	c.1000G>A	p.Gly334Ser	missense_variant	Exon 4 of 8		NM_001286554.2	ENSP00000507239.1	Q70CQ1-1
USP49	ENST00000373010.5 link	c.1000G>A	p.Gly334Ser	missense_variant	Exon 6 of 10	5		ENSP00000362101.1	Q5T3E1
ENSG00000288721	ENST00000684631.1 link	n.*1158G>A		non_coding_transcript_exon_variant	Exon 6 of 10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1 link	n.*1158G>A		3_prime_UTR_variant	Exon 6 of 10			ENSP00000507261.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

9.6

DANN

Benign

0.87

DEOGEN2

Benign

0.075

T;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.54

T;T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;L

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Benign

0.12

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.069

T;T;T

Polyphen

0.41

.;.;B

Vest4

0.064

MutPred

0.60

Gain of disorder (P = 0.0434);Gain of disorder (P = 0.0434);Gain of disorder (P = 0.0434);

MVP

0.15

MPC

0.76

ClinPred

0.53

GERP RS

1.2

Varity_R

0.11

gMVP

0.41

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