21-29038357-T-C

Variant names:

• chr21-29038357-T-C
• NM_006447.3:c.659T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006447.3(USP16):​c.659T>C​(p.Leu220Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,256 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP16 NM_006447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

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

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, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP16	NM_006447.3	c.659T>C	p.Leu220Pro	missense_variant	Exon 7 of 18	ENST00000399976.7	NP_006438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP16	ENST00000399976.7	c.659T>C	p.Leu220Pro	missense_variant	Exon 7 of 18	1	NM_006447.3	ENSP00000382858.2
USP16	ENST00000399975.7	c.656T>C	p.Leu219Pro	missense_variant	Exon 7 of 18	1		ENSP00000382857.3
USP16	ENST00000474835.5	n.827T>C		non_coding_transcript_exon_variant	Exon 7 of 17	1
USP16	ENST00000334352.8	c.659T>C	p.Leu220Pro	missense_variant	Exon 8 of 19	5		ENSP00000334808.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460256 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.659T>C (p.L220P) alteration is located in exon 8 (coding exon 6) of the USP16 gene. This alteration results from a T to C substitution at nucleotide position 659, causing the leucine (L) at amino acid position 220 to be replaced by a proline (P). 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	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	.;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.6	.;H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.95		.;Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);
MVP		0.56
MPC		0.56
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-30410678;