Variant 6-41805863-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001286554.2(USP49):c.1121C>T(p.Ala374Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

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: 9.92

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 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
USP49	NM_001286554.2 linkuse as main transcript	c.1121C>T	p.Ala374Val	missense_variant	4/8	ENST00000682992.1	NP_001273483.1	Q70CQ1-1
USP49	NM_001384542.1 linkuse as main transcript	c.1121C>T	p.Ala374Val	missense_variant	4/8		NP_001371471.1
USP49	NM_018561.5 linkuse as main transcript	c.1121C>T	p.Ala374Val	missense_variant	4/7		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.1121C>T	p.Ala374Val	missense_variant	4/8		NM_001286554.2	ENSP00000507239.1	Q70CQ1-1
USP49	ENST00000373010.5 linkuse as main transcript	c.1121C>T	p.Ala374Val	missense_variant	6/10	5		ENSP00000362101.1	Q5T3E1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*1279C>T		non_coding_transcript_exon_variant	6/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*1279C>T		3_prime_UTR_variant	6/10			ENSP00000507261.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

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

May 04, 2022

The c.1121C>T (p.A374V) alteration is located in exon 4 (coding exon 1) of the USP49 gene. This alteration results from a C to T substitution at nucleotide position 1121, causing the alanine (A) at amino acid position 374 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

0.27

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.087

T;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Uncertain

-0.068

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.048

D;T;T

Polyphen

1.0

.;.;D

Vest4

0.45

MutPred

0.54

Loss of ubiquitination at K372 (P = 0.0962);Loss of ubiquitination at K372 (P = 0.0962);Loss of ubiquitination at K372 (P = 0.0962);

MVP

0.47

MPC

1.6

ClinPred

0.98

GERP RS

5.3

Varity_R

0.56

gMVP

0.57

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