Genetic Variant NM_006447.3:c.983G>T (chr21-29040640-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006447.3(USP16):c.983G>T(p.Gly328Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G328A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

USP16
NM_006447.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16691408).

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.983G>T	p.Gly328Val	missense	Exon 10 of 18	NP_006438.1	Q9Y5T5-1
USP16	NM_001032410.2		c.983G>T	p.Gly328Val	missense	Exon 11 of 19	NP_001027582.1	Q9Y5T5-1
USP16	NM_001001992.2		c.980G>T	p.Gly327Val	missense	Exon 10 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.983G>T	p.Gly328Val	missense	Exon 10 of 18	ENSP00000382858.2	Q9Y5T5-1
USP16	ENST00000399975.7	TSL:1	c.980G>T	p.Gly327Val	missense	Exon 10 of 18	ENSP00000382857.3	Q9Y5T5-2
USP16	ENST00000474835.5	TSL:1	n.1151G>T		non_coding_transcript_exon	Exon 10 of 17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1390878

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694184

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31506

American (AMR)

AF:

0.00

AC:

AN:

41882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24814

East Asian (EAS)

AF:

0.00

AC:

AN:

37956

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5544

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057798

Other (OTH)

AF:

0.00

AC:

AN:

57236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.064

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.011

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

PhyloP100

1.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.074

Sift

Benign

0.043

Sift4G

Uncertain

0.044

Polyphen

0.19

Vest4

0.32

MutPred

0.42

Loss of disorder (P = 0.0536)

MVP

0.35

MPC

0.39

ClinPred

0.94

GERP RS

2.6

Varity_R

0.14

gMVP

0.54

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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