chr4-52593565-A-G

Position:

• chr4-52593565-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022832.4(USP46):​c.*4075T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,270 control chromosomes in the GnomAD database, including 3,021 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (3020 hom., cov: 33)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: USP46 NM_022832.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02

Genes affected

USP46 (HGNC:20075): (ubiquitin specific peptidase 46) Modification of cellular proteins by ubiquitin is an essential regulatory mechanism controlled by the coordinated action of multiple ubiquitin-conjugating and deubiquitinating enzymes. USP46 belongs to a large family of cysteine proteases that function as deubiquitinating enzymes (Quesada et al., 2004 [PubMed 14715245]).[supplied by OMIM, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP46	NM_022832.4	c.*4075T>C		3_prime_UTR_variant	9/9	ENST00000441222.8	NP_073743.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP46	ENST00000441222.8	c.*4075T>C		3_prime_UTR_variant	9/9	1	NM_022832.4	ENSP00000407818	P1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27244 AN: 152112 Hom.: 2995 Cov.: 33

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.125 AC: 5 AN: 40 Hom.: 1 Cov.: 0 AF XY: 0.133 AC XY: 4 AN XY: 30

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0588

GnomAD4 genome AF: 0.180 AC: 27327 AN: 152230 Hom.: 3020 Cov.: 33 AF XY: 0.178 AC XY: 13274 AN XY: 74434

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.175

Alfa AF: 0.156 Hom.: 395

Bravo AF: 0.191

Asia WGS AF: 0.170 AC: 592 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.35
DANN	Benign	0.45

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: rs10034164; hg19: chr4-53459731;