rs2244291

Variant names:

• chr4-52602313-T-C
• rs2244291
• NM_022832.4:c.723-259A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022832.4(USP46):​c.723-259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0927 in 152,166 control chromosomes in the GnomAD database, including 856 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 0.093 (856 hom., cov: 32)
• Consequence: USP46 NM_022832.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP46	NM_022832.4	c.723-259A>G		intron_variant	Intron 6 of 8	ENST00000441222.8	NP_073743.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP46	ENST00000441222.8	c.723-259A>G		intron_variant	Intron 6 of 8	1	NM_022832.4	ENSP00000407818.2

Frequencies

GnomAD3 genomes AF: 0.0928 AC: 14108 AN: 152048 Hom.: 854 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0828

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

GnomAD4 genome AF: 0.0927 AC: 14104 AN: 152166 Hom.: 856 Cov.: 32 AF XY: 0.0965 AC XY: 7175 AN XY: 74362

African (AFR) AF: 0.0192 AC: 798 AN: 41556

American (AMR) AF: 0.124 AC: 1894 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1108 AN: 5164

South Asian (SAS) AF: 0.159 AC: 765 AN: 4818

European-Finnish (FIN) AF: 0.160 AC: 1686 AN: 10570

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7253 AN: 67996

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0951 Hom.: 1472

Bravo AF: 0.0858

Asia WGS AF: 0.193 AC: 671 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.57
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs2244291; hg19: chr4-53468479;