Genetic Variant USP16:p.Pro186Leu (chr21-29037384-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_006447.3(USP16):c.557C>T(p.Pro186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,278 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

USP16
NM_006447.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

USP16 (HGNC:12614): (ubiquitin specific peptidase 16) This gene encodes a deubiquitinating enzyme that is phosphorylated at the onset of mitosis and then dephosphorylated at the metaphase/anaphase transition. It can deubiquitinate H2A, one of two major ubiquitinated proteins of chromatin, in vitro and a mutant form of the protein was shown to block cell division. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP16 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=0.06983036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP16	NM_006447.3 link	c.557C>T	p.Pro186Leu	missense_variant	Exon 6 of 18	ENST00000399976.7	NP_006438.1	Q9Y5T5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP16	ENST00000399976.7 link	c.557C>T	p.Pro186Leu	missense_variant	Exon 6 of 18	1	NM_006447.3	ENSP00000382858.2	Q9Y5T5-1
USP16	ENST00000399975.7 link	c.554C>T	p.Pro185Leu	missense_variant	Exon 6 of 18	1		ENSP00000382857.3	Q9Y5T5-2
USP16	ENST00000474835.5 link	n.725C>T		non_coding_transcript_exon_variant	Exon 6 of 17	1
USP16	ENST00000334352.8 link	c.557C>T	p.Pro186Leu	missense_variant	Exon 7 of 19	5		ENSP00000334808.4	Q9Y5T5-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457182

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557C>T (p.P186L) alteration is located in exon 7 (coding exon 5) of the USP16 gene. This alteration results from a C to T substitution at nucleotide position 557, causing the proline (P) at amino acid position 186 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

0.065

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.29

DEOGEN2

Benign

0.040

.;T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.76

T;.;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.070

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

.;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.089

B;B;B

Vest4

0.10

MutPred

0.16

.;Loss of glycosylation at P186 (P = 0.0177);Loss of glycosylation at P186 (P = 0.0177);

MVP

0.25

MPC

0.087

ClinPred

0.064

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.18

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