Variant 6-41806027-A-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.957T>G(p.Asn319Lys) 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. 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: 32)

Consequence

USP49
NM_001286554.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0760

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=0.027285308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP49	NM_001286554.2 linkuse as main transcript	c.957T>G	p.Asn319Lys	missense_variant	4/8	ENST00000682992.1	NP_001273483.1	Q70CQ1-1
USP49	NM_001384542.1 linkuse as main transcript	c.957T>G	p.Asn319Lys	missense_variant	4/8		NP_001371471.1
USP49	NM_018561.5 linkuse as main transcript	c.957T>G	p.Asn319Lys	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.957T>G	p.Asn319Lys	missense_variant	4/8		NM_001286554.2	ENSP00000507239.1	Q70CQ1-1
USP49	ENST00000373010.5 linkuse as main transcript	c.957T>G	p.Asn319Lys	missense_variant	6/10	5		ENSP00000362101.1	Q5T3E1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*1115T>G		non_coding_transcript_exon_variant	6/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*1115T>G		3_prime_UTR_variant	6/10			ENSP00000507261.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250598

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Oct 05, 2022

The c.957T>G (p.N319K) alteration is located in exon 4 (coding exon 1) of the USP49 gene. This alteration results from a T to G substitution at nucleotide position 957, causing the asparagine (N) at amino acid position 319 to be replaced by a lysine (K). 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

0.095

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.43

DANN

Benign

0.29

DEOGEN2

Benign

0.0067

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.50

T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.65

N;.;N

PrimateAI

Benign

0.34

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.024

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0040

.;.;B

Vest4

0.11

MutPred

0.40

Gain of ubiquitination at N319 (P = 7e-04);Gain of ubiquitination at N319 (P = 7e-04);Gain of ubiquitination at N319 (P = 7e-04);

MVP

0.082

MPC

0.88

ClinPred

0.031

GERP RS

0.95

Varity_R

0.033

gMVP

0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over