4-52628116-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_022832.4(USP46):c.165C>T(p.Phe55=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00209 in 1,613,950 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (23 hom.)
• Consequence: USP46 NM_022832.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.43

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=-0.32).
• BP6: Variant 4-52628116-G-A is Benign according to our data. Variant chr4-52628116-G-A is described in ClinVar as [Benign]. Clinvar id is 769633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00952 (1450/152300) while in subpopulation AFR AF= 0.0327 (1359/41536). AF 95% confidence interval is 0.0313. There are 19 homozygotes in gnomad4. There are 693 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP46	NM_022832.4	c.165C>T	p.Phe55=	synonymous_variant	3/9	ENST00000441222.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP46	ENST00000441222.8	c.165C>T	p.Phe55=	synonymous_variant	3/9	1	NM_022832.4	P1

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1448 AN: 152182 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00267 AC: 664 AN: 248974 Hom.: 5 AF XY: 0.00202 AC XY: 273 AN XY: 135056

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000496

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00132 AC: 1929 AN: 1461650 Hom.: 23 Cov.: 31 AF XY: 0.00110 AC XY: 802 AN XY: 727098

Gnomad4 AFR exome AF: 0.0340

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000497

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00952 AC: 1450 AN: 152300 Hom.: 19 Cov.: 32 AF XY: 0.00931 AC XY: 693 AN XY: 74476

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00553 Hom.: 4

Bravo AF: 0.0107

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	12
Dann	Benign	0.85

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: rs115007179; hg19: chr4-53494283;