rs17675844

chr4-52624583-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022832.4(USP46):c.561+1435A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 152,288 control chromosomes in the GnomAD database, including 76 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 0.023 (76 hom., cov: 32)
• Consequence: USP46 NM_022832.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.642

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=-0.89).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0231 (3519/152288) while in subpopulation AMR AF= 0.051 (781/15302). AF 95% confidence interval is 0.0481. There are 76 homozygotes in gnomad4. There are 1743 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 75 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP46	NM_022832.4	c.561+1435A>C		intron_variant		ENST00000441222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP46	ENST00000441222.8	c.561+1435A>C		intron_variant		1	NM_022832.4	P1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3518 AN: 152170 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0510

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0231 AC: 3519 AN: 152288 Hom.: 76 Cov.: 32 AF XY: 0.0234 AC XY: 1743 AN XY: 74476

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.0510

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.0508

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0219 Hom.: 8

Bravo AF: 0.0260

Asia WGS AF: 0.0270 AC: 92 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.7
Dann	Benign	0.63

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: rs17675844; hg19: chr4-53490750;