chr4-52624583-T-G

Variant names:

• chr4-52624583-T-G
• rs17675844
• NM_022832.4:c.561+1435A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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=-0.89).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022832.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP46	NM_022832.4	MANE Select	c.561+1435A>C		intron	N/A	NP_073743.2
	USP46	NM_001134223.2		c.540+1435A>C		intron	N/A	NP_001127695.1
	USP46	NM_001286767.2		c.525+1435A>C		intron	N/A	NP_001273696.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP46	ENST00000441222.8	TSL:1 MANE Select	c.561+1435A>C		intron	N/A	ENSP00000407818.2
	USP46	ENST00000508499.5	TSL:2	c.540+1435A>C		intron	N/A	ENSP00000423244.1
	USP46	ENST00000451218.6	TSL:5	c.480+1435A>C		intron	N/A	ENSP00000390102.2

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

African (AFR) AF: 0.00520 AC: 216 AN: 41564

American (AMR) AF: 0.0510 AC: 781 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.0508 AC: 263 AN: 5182

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4826

European-Finnish (FIN) AF: 0.0324 AC: 344 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1736 AN: 68018

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.63
PhyloP100		-0.64
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: rs17675844; hg19: chr4-53490750; COSMIC: COSV107528844; COSMIC: COSV107528844;