NM_032172.3:c.566A>T

Variant names:

• chr7-6139104-A-T
• NM_032172.3:c.566A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032172.3(USP42):​c.566A>T​(p.His189Leu) 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: USP42 NM_032172.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89
• Publications: 0 publications found

Genes affected

USP42 (HGNC:20068): (ubiquitin specific peptidase 42) Enables 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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP42	NM_032172.3	c.566A>T	p.His189Leu	missense_variant	Exon 5 of 18	ENST00000306177.10	NP_115548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP42	ENST00000306177.10	c.566A>T	p.His189Leu	missense_variant	Exon 5 of 18	5	NM_032172.3	ENSP00000301962.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566A>T (p.H189L) alteration is located in exon 5 (coding exon 4) of the USP42 gene. This alteration results from a A to T substitution at nucleotide position 566, causing the histidine (H) at amino acid position 189 to be replaced by a leucine (L). 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
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.021	.;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		8.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.66
MutPred		0.55		Loss of disorder (P = 0.0559);.;.;
MVP		0.41
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.74
Mutation Taster		=43/57	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

hg19: chr7-6178735;