17-9645720-C-T

Variant names:

• chr17-9645720-C-T
• rs1434204489
• NM_153210.5:c.88C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153210.5(USP43):​c.88C>T​(p.Arg30Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000663 in 1,206,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: USP43 NM_153210.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.912

Genes affected

USP43 (HGNC:20072): (ubiquitin specific peptidase 43) Predicted to enable ISG15-specific protease activity. Predicted to be involved in translesion synthesis. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CFAP52 (HGNC:16053): (cilia and flagella associated protein 52) WD repeat-containing proteins, such as WDR16, play crucial roles in a wide range of physiologic functions, including signal transduction, RNA processing, remodeling the cytoskeleton, regulation of vesicular traffic, and cell division (Silva et al., 2005 [PubMed 15967112]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41628936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP43	NM_153210.5	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 15	ENST00000285199.12	NP_694942.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP43	ENST00000285199.12	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 15	1	NM_153210.5	ENSP00000285199.6
USP43	ENST00000570475.5	c.88C>T	p.Arg30Cys	missense_variant	Exon 1 of 15	1		ENSP00000458963.1
USP43	ENST00000570827.6	n.645+378C>T		intron_variant	Intron 1 of 14	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000663 AC: 8 AN: 1206888 Hom.: 0 Cov.: 30 AF XY: 0.00000339 AC XY: 2 AN XY: 589398

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: 0.00000805

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88C>T (p.R30C) alteration is located in exon 1 (coding exon 1) of the USP43 gene. This alteration results from a C to T substitution at nucleotide position 88, causing the arginine (R) at amino acid position 30 to be replaced by a cysteine (C). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.6	.;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.24
MutPred		0.47		Loss of methylation at R30 (P = 0.0262);Loss of methylation at R30 (P = 0.0262);
MVP		0.60
MPC		0.68
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.38
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1434204489; hg19: chr17-9549037;