21-29037330-G-A

Variant names:

• chr21-29037330-G-A
• NM_006447.3:c.503G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006447.3(USP16):​c.503G>A​(p.Ser168Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,430,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: USP16 NM_006447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.270

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047422856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP16	NM_006447.3	c.503G>A	p.Ser168Asn	missense_variant	Exon 6 of 18	ENST00000399976.7	NP_006438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP16	ENST00000399976.7	c.503G>A	p.Ser168Asn	missense_variant	Exon 6 of 18	1	NM_006447.3	ENSP00000382858.2
USP16	ENST00000399975.7	c.500G>A	p.Ser167Asn	missense_variant	Exon 6 of 18	1		ENSP00000382857.3
USP16	ENST00000474835.5	n.671G>A		non_coding_transcript_exon_variant	Exon 6 of 17	1
USP16	ENST00000334352.8	c.503G>A	p.Ser168Asn	missense_variant	Exon 7 of 19	5		ENSP00000334808.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1430930 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 712222

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: 0.00

Gnomad4 NFE exome AF: 0.00000457

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503G>A (p.S168N) alteration is located in exon 7 (coding exon 5) of the USP16 gene. This alteration results from a G to A substitution at nucleotide position 503, causing the serine (S) at amino acid position 168 to be replaced by an asparagine (N). 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	Benign	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.053	.;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0095
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.70	T;.;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.32	B;B;B
Vest4		0.077
MutPred		0.24		.;Loss of phosphorylation at S168 (P = 0.0035);Loss of phosphorylation at S168 (P = 0.0035);
MVP		0.26
MPC		0.073
ClinPred		0.21	T
GERP RS		5.0
Varity_R		0.042
gMVP		0.24

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: chr21-30409651;