Genetic Variant NM_006447.3:c.601T>A (chr21-29037428-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006447.3(USP16):c.601T>A(p.Leu201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,324 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

USP16
NM_006447.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006447.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP16	NM_006447.3	MANE Select	c.601T>A	p.Leu201Met	missense	Exon 6 of 18	NP_006438.1	Q9Y5T5-1
USP16	NM_001032410.2		c.601T>A	p.Leu201Met	missense	Exon 7 of 19	NP_001027582.1	Q9Y5T5-1
USP16	NM_001001992.2		c.598T>A	p.Leu200Met	missense	Exon 6 of 18	NP_001001992.1	Q9Y5T5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP16	ENST00000399976.7	TSL:1 MANE Select	c.601T>A	p.Leu201Met	missense	Exon 6 of 18	ENSP00000382858.2	Q9Y5T5-1
USP16	ENST00000399975.7	TSL:1	c.598T>A	p.Leu200Met	missense	Exon 6 of 18	ENSP00000382857.3	Q9Y5T5-2
USP16	ENST00000474835.5	TSL:1	n.769T>A		non_coding_transcript_exon	Exon 6 of 17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447324

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32612

American (AMR)

AF:

0.00

AC:

AN:

41686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

39456

South Asian (SAS)

AF:

0.00

AC:

AN:

81556

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107632

Other (OTH)

AF:

0.00

AC:

AN:

59800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.3

PhyloP100

1.5

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.8

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.71

MutPred

0.80

Gain of disorder (P = 0.0621)

MVP

0.38

MPC

0.44

ClinPred

0.98

GERP RS

4.7

Varity_R

0.51

gMVP

0.48

Mutation Taster

=95/5

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over