Genetic Variant USP21:p.Leu144Phe (chr1-161161070-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001014443.3(USP21):c.430C>T(p.Leu144Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 1 hom. )

Consequence

USP21
NM_001014443.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

USP21 (HGNC:12620): (ubiquitin specific peptidase 21) This gene encodes a member of the C19 peptidase family, also known as family 2 of ubiquitin carboxy-terminal hydrolases. The encoded protein cleaves ubiquitin from ubiquitinated proteins for recycling in intracellular protein degradation. The encoded protein is also able to release NEDD8, a ubiquitin-like protein, from NEDD8-conjugated proteins. This gene has been referred to as USP16 and USP23 but is now known as USP21. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

USP21 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26532644).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP21	NM_001014443.3 link	c.430C>T	p.Leu144Phe	missense_variant	Exon 3 of 14	ENST00000368002.8	NP_001014443.1	Q9UK80-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP21	ENST00000368002.8 link	c.430C>T	p.Leu144Phe	missense_variant	Exon 3 of 14	1	NM_001014443.3	ENSP00000356981.3	Q9UK80-1
USP21	ENST00000289865.12 link	c.430C>T	p.Leu144Phe	missense_variant	Exon 2 of 13	1		ENSP00000289865.8	Q9UK80-1
USP21	ENST00000368001.1 link	c.430C>T	p.Leu144Phe	missense_variant	Exon 2 of 13	1		ENSP00000356980.1	Q9UK80-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251324

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.430C>T (p.L144F) alteration is located in exon 3 (coding exon 1) of the USP21 gene. This alteration results from a C to T substitution at nucleotide position 430, causing the leucine (L) at amino acid position 144 to be replaced by a phenylalanine (F). 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

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

.;T;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;.;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.55

.;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.28

.;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0020

.;D;D;D

Sift4G

Pathogenic

0.0

D;T;T;T

Polyphen

0.99

.;D;D;.

Vest4

0.47, 0.39, 0.39

MutPred

0.26

Gain of methylation at R145 (P = 0.1213);Gain of methylation at R145 (P = 0.1213);Gain of methylation at R145 (P = 0.1213);Gain of methylation at R145 (P = 0.1213);

MVP

0.68

MPC

0.55

ClinPred

0.27

GERP RS

4.9

Varity_R

0.19

gMVP

0.51

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