rs146758743

chr15-91013804-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_018668.5(VPS33B):c.357G>A(p.Lys119=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00127 in 1,614,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: VPS33B NM_018668.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.00

Genes affected

VPS33B (HGNC:12712): (VPS33B late endosome and lysosome associated) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 15-91013804-C-T is Benign according to our data. Variant chr15-91013804-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-91013804-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00119 (182/152304) while in subpopulation AMR AF= 0.00516 (79/15300). AF 95% confidence interval is 0.00425. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.357G>A	p.Lys119=	splice_region_variant, synonymous_variant	5/23	ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.357G>A	p.Lys119=	splice_region_variant, synonymous_variant	5/23	1	NM_018668.5	P1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00206 AC: 518 AN: 251488 Hom.: 3 AF XY: 0.00173 AC XY: 235 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00128 AC: 1870 AN: 1461858 Hom.: 5 Cov.: 31 AF XY: 0.00116 AC XY: 847 AN XY: 727234

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00825

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74478

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00216

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.090
Cadd	Benign	21
Dann	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.11		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: rs146758743; hg19: chr15-91557034;