13-27116571-T-C

Variant names:

• chr13-27116571-T-C
• rs780773716
• NM_182488.4:c.74A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_182488.4(USP12):​c.74A>G​(p.Lys25Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: USP12 NM_182488.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93
• Publications: 0 publications found

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]

USP12-AS1 (HGNC:39961): (USP12 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36559933).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182488.4. 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
	USP12	NM_182488.4	MANE Select	c.74A>G	p.Lys25Arg	missense	Exon 2 of 9	NP_872294.2	O75317

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP12	ENST00000282344.11	TSL:1 MANE Select	c.74A>G	p.Lys25Arg	missense	Exon 2 of 9	ENSP00000282344.6	O75317
	USP12	ENST00000963737.1		c.74A>G	p.Lys25Arg	missense	Exon 2 of 9	ENSP00000633796.1
	USP12	ENST00000915651.1		c.49-10627A>G		intron	N/A	ENSP00000585710.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460526 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726578

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 31

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	Benign	0.11
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	0.0030
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Benign	0.21	T
Sift4G	Benign	0.13	T
Polyphen		0.090	B
Vest4		0.64
MutPred		0.32		Loss of ubiquitination at K25 (P = 0.0043)
MVP		0.36
MPC		0.81
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.45
gMVP		0.39
Mutation Taster		=49/51	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: rs780773716; hg19: chr13-27690708;