21-29037365-A-G

Variant names:

• chr21-29037365-A-G
• NM_006447.3:c.538A>G

Variant summary

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

The NM_006447.3(USP16):​c.538A>G​(p.Met180Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,457,418 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: 0.0000069 (0 hom.)
• Consequence: USP16 NM_006447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0870

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=0.03569436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP16	NM_006447.3	c.538A>G	p.Met180Val	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.538A>G	p.Met180Val	missense_variant	Exon 6 of 18	1	NM_006447.3	ENSP00000382858.2
USP16	ENST00000399975.7	c.535A>G	p.Met179Val	missense_variant	Exon 6 of 18	1		ENSP00000382857.3
USP16	ENST00000474835.5	n.706A>G		non_coding_transcript_exon_variant	Exon 6 of 17	1
USP16	ENST00000334352.8	c.538A>G	p.Met180Val	missense_variant	Exon 7 of 19	5		ENSP00000334808.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457418 Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7 AN XY: 724912

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: 0.00000901

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

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538A>G (p.M180V) alteration is located in exon 7 (coding exon 5) of the USP16 gene. This alteration results from a A to G substitution at nucleotide position 538, causing the methionine (M) at amino acid position 180 to be replaced by a valine (V). 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	0.055
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.3
DANN	Benign	0.76
DEOGEN2	Benign	0.030	.;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	T;.;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.090	N;N;N
REVEL	Benign	0.028
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.056
MutPred		0.16		.;Gain of methylation at K176 (P = 0.1407);Gain of methylation at K176 (P = 0.1407);
MVP		0.15
MPC		0.079
ClinPred		0.024	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.18

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: chr21-30409686;