rs766867815

Variant names:

• chr21-29030603-T-A
• rs766867815
• NM_006447.3:c.70T>A

Your query was ambiguous. Multiple possible variants found:

• chr21-29030603-T-A
• chr21-29030603-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006447.3(USP16):​c.70T>A​(p.Cys24Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000499 in 1,603,458 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: USP16 NM_006447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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.70T>A	p.Cys24Ser	missense	Exon 3 of 18	NP_006438.1	Q9Y5T5-1
	USP16	NM_001032410.2		c.70T>A	p.Cys24Ser	missense	Exon 4 of 19	NP_001027582.1	Q9Y5T5-1
	USP16	NM_001001992.2		c.70T>A	p.Cys24Ser	missense	Exon 3 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.70T>A	p.Cys24Ser	missense	Exon 3 of 18	ENSP00000382858.2	Q9Y5T5-1
	USP16	ENST00000399975.7	TSL:1	c.70T>A	p.Cys24Ser	missense	Exon 3 of 18	ENSP00000382857.3	Q9Y5T5-2
	USP16	ENST00000474835.5	TSL:1	n.238T>A		non_coding_transcript_exon	Exon 3 of 17

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000827 AC: 2 AN: 241938 AF XY: 0.0000153

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451218 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721828

African (AFR) AF: 0.0000306 AC: 1 AN: 32694

American (AMR) AF: 0.00 AC: 0 AN: 42072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 83856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108646

Other (OTH) AF: 0.00 AC: 0 AN: 59852

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74386

African (AFR) AF: 0.000169 AC: 7 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.83		Gain of disorder (P = 0.0072)
MVP		0.99
MPC		0.49
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.81
Mutation Taster		=30/70	disease causing

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: rs766867815; hg19: chr21-30402924;