Genetic Variant USP19:p.Thr1298Met (chr3-49110329-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001199161.2(USP19):c.3893C>T(p.Thr1298Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000181 in 1,601,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.000018 ( 0 hom. )

Consequence

USP19
NM_001199161.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.87

Publications

0 publications found

Variant links:

Genes affected

USP19 (HGNC:12617): (ubiquitin specific peptidase 19) Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. This dynamic process, involving ubiquitin conjugating enzymes and deubiquitinating enzymes, adds and removes ubiquitin. Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. This protein is a ubiquitin protein ligase and plays a role in muscle wasting. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2017]

USP19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24703208).

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP19	NM_001199161.2 link	c.3893C>T	p.Thr1298Met	missense_variant	Exon 26 of 27	ENST00000417901.6	NP_001186090.1	O94966-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP19	ENST00000417901.6 link	c.3893C>T	p.Thr1298Met	missense_variant	Exon 26 of 27	1	NM_001199161.2	ENSP00000395260.1		O94966-6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000376

AC:

AN:

239436

AF XY:

0.0000231

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.0000599

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1449082

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

719314

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33262

American (AMR)

AF:

0.0000687

AC:

AN:

43668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25244

East Asian (EAS)

AF:

0.000101

AC:

AN:

39530

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00000815

AC:

AN:

1104234

Other (OTH)

AF:

0.0000501

AC:

AN:

59836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000663

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000233

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3887C>T (p.T1296M) alteration is located in exon 26 (coding exon 25) of the USP19 gene. This alteration results from a C to T substitution at nucleotide position 3887, causing the threonine (T) at amino acid position 1296 to be replaced by a methionine (M). 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

0.068

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

.;.;.;T;T;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;T;T;.;D;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.25

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

.;.;.;.;L;.

PhyloP100

3.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.2

N;N;N;N;N;N

REVEL

Benign

0.092

Sift

Benign

0.14

T;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T

Polyphen

1.0, 0.33

.;.;.;D;B;.

Vest4

0.22

MVP

0.24

MPC

0.61

ClinPred

0.069

GERP RS

4.8

Varity_R

0.12

gMVP

0.28

Mutation Taster

=62/38

polymorphism

(source)

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

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3-49110329-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over