6-41806322-G-A

Position:

chr6-41806322-G-A

Variant summary

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

The NM_001286554.2(USP49):c.662C>T(p.Pro221Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,547,972 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

USP49
NM_001286554.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.159

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07216701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP49	NM_001286554.2 linkuse as main transcript	c.662C>T	p.Pro221Leu	missense_variant	4/8	ENST00000682992.1	NP_001273483.1	Q70CQ1-1
USP49	NM_001384542.1 linkuse as main transcript	c.662C>T	p.Pro221Leu	missense_variant	4/8		NP_001371471.1
USP49	NM_018561.5 linkuse as main transcript	c.662C>T	p.Pro221Leu	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.662C>T	p.Pro221Leu	missense_variant	4/8		NM_001286554.2	ENSP00000507239.1	Q70CQ1-1
USP49	ENST00000373010.5 linkuse as main transcript	c.662C>T	p.Pro221Leu	missense_variant	6/10	5		ENSP00000362101.1	Q5T3E1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*820C>T		non_coding_transcript_exon_variant	6/10			ENSP00000507261.1
ENSG00000288721	ENST00000684631.1 linkuse as main transcript	n.*820C>T		3_prime_UTR_variant	6/10			ENSP00000507261.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

167516

Hom.:

AF XY:

0.0000214

AC XY:

AN XY:

93288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000121

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000430

AC:

AN:

1395762

Hom.:

Cov.:

AF XY:

0.00000434

AC XY:

AN XY:

690880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

0.00000184

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000910

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

Feb 14, 2023

The c.662C>T (p.P221L) 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 662, causing the proline (P) at amino acid position 221 to be replaced by a leucine (L). 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

0.084

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.032

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.46

T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.55

N;.;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.051

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0010

.;.;B

Vest4

0.032

MutPred

0.34

Gain of stability (P = 0.0205);Gain of stability (P = 0.0205);Gain of stability (P = 0.0205);

MVP

0.043

MPC

1.0

ClinPred

0.034

GERP RS

0.43

Varity_R

0.031

gMVP

0.55

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