13-27075282-G-A

Variant names:

• chr13-27075282-G-A
• NM_182488.4:c.841C>T

Variant summary

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

The NM_182488.4(USP12):​c.841C>T​(p.Pro281Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: USP12 NM_182488.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.84

Genes affected

USP12 (HGNC:20485): (ubiquitin specific peptidase 12) Enables cysteine-type endopeptidase activity and thiol-dependent deubiquitinase. Involved in protein deubiquitination. Predicted to be located in nucleoplasm. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP12	NM_182488.4	c.841C>T	p.Pro281Ser	missense_variant	Exon 7 of 9	ENST00000282344.11	NP_872294.2
USP12	XM_005266282.3	c.841C>T	p.Pro281Ser	missense_variant	Exon 7 of 8		XP_005266339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP12	ENST00000282344.11	c.841C>T	p.Pro281Ser	missense_variant	Exon 7 of 9	1	NM_182488.4	ENSP00000282344.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841C>T (p.P281S) alteration is located in exon 7 (coding exon 7) of the USP12 gene. This alteration results from a C to T substitution at nucleotide position 841, causing the proline (P) at amino acid position 281 to be replaced by a serine (S). 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	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.90		Gain of MoRF binding (P = 0.0434);
MVP		0.56
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr13-27649419;