rs6554557

Positions:

• chr4-52621374-T-G

Variant summary

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

The NM_022832.4(USP46):​c.561+4644A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,164 control chromosomes in the GnomAD database, including 3,142 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 (3142 hom., cov: 33)
• Consequence: USP46 NM_022832.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP46	NM_022832.4	c.561+4644A>C		intron_variant		ENST00000441222.8	NP_073743.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP46	ENST00000441222.8	c.561+4644A>C		intron_variant		1	NM_022832.4	ENSP00000407818	P1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27636 AN: 152046 Hom.: 3114 Cov.: 33

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.182 AC: 27724 AN: 152164 Hom.: 3142 Cov.: 33 AF XY: 0.181 AC XY: 13467 AN XY: 74390

Gnomad4 AFR AF: 0.333

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.178

Alfa AF: 0.158 Hom.: 407

Bravo AF: 0.194

Asia WGS AF: 0.172 AC: 597 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.91
DANN	Benign	0.23

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: rs6554557; hg19: chr4-53487541;