Genetic Variant USP16:p.Pro278Leu (chr21-29039126-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006447.3(USP16):c.833C>T(p.Pro278Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000444 in 1,577,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

USP16
NM_006447.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP16	NM_006447.3 link	c.833C>T	p.Pro278Leu	missense_variant	Exon 8 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.833C>T	p.Pro278Leu	missense_variant	Exon 8 of 18	1	NM_006447.3	ENSP00000382858.2	Q9Y5T5-1
USP16	ENST00000399975.7 link	c.830C>T	p.Pro277Leu	missense_variant	Exon 8 of 18	1		ENSP00000382857.3	Q9Y5T5-2
USP16	ENST00000474835.5 link	n.1001C>T		non_coding_transcript_exon_variant	Exon 8 of 17	1
USP16	ENST00000334352.8 link	c.833C>T	p.Pro278Leu	missense_variant	Exon 9 of 19	5		ENSP00000334808.4	Q9Y5T5-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152000

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

234762

Hom.:

AF XY:

0.00000783

AC XY:

AN XY:

127722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000608

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000421

AC:

AN:

1425412

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000264

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000458

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74230

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.833C>T (p.P278L) alteration is located in exon 9 (coding exon 7) of the USP16 gene. This alteration results from a C to T substitution at nucleotide position 833, causing the proline (P) at amino acid position 278 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

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;.;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-9.1

D;D;D

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.92

MutPred

0.89

.;Loss of disorder (P = 0.0301);Loss of disorder (P = 0.0301);

MVP

0.57

MPC

0.45

ClinPred

0.97

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.85

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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