21-29039053-C-T

Variant names:

• chr21-29039053-C-T
• rs565573891
• NM_006447.3:c.760C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006447.3(USP16):​c.760C>T​(p.Pro254Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P254A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: USP16 NM_006447.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.73
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2909944).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP16	NM_006447.3	MANE Select	c.760C>T	p.Pro254Ser	missense	Exon 8 of 18	NP_006438.1	Q9Y5T5-1
	USP16	NM_001032410.2		c.760C>T	p.Pro254Ser	missense	Exon 9 of 19	NP_001027582.1	Q9Y5T5-1
	USP16	NM_001001992.2		c.757C>T	p.Pro253Ser	missense	Exon 8 of 18	NP_001001992.1	Q9Y5T5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP16	ENST00000399976.7	TSL:1 MANE Select	c.760C>T	p.Pro254Ser	missense	Exon 8 of 18	ENSP00000382858.2	Q9Y5T5-1
	USP16	ENST00000399975.7	TSL:1	c.757C>T	p.Pro253Ser	missense	Exon 8 of 18	ENSP00000382857.3	Q9Y5T5-2
	USP16	ENST00000474835.5	TSL:1	n.928C>T		non_coding_transcript_exon	Exon 8 of 17

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD2 exomes AF: 0.00000431 AC: 1 AN: 231820 AF XY: 0.00000793

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000620

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74442

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

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.30
Sift	Benign	0.056	T
Sift4G	Benign	0.093	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.42		Loss of catalytic residue at P253 (P = 0.0117)
MVP		0.37
MPC		0.45
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.48
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs565573891; hg19: chr21-30411374;