rs11542639

chr15-91022257-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018668.5(VPS33B):c.-8C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,555,120 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (21 hom.)
• Consequence: VPS33B NM_018668.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.59

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 15-91022257-G-A is Benign according to our data. Variant chr15-91022257-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1601/152306) while in subpopulation AFR AF= 0.0349 (1450/41552). AF 95% confidence interval is 0.0334. There are 19 homozygotes in gnomad4. There are 772 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.-8C>T		5_prime_UTR_variant	1/23	ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.-8C>T		5_prime_UTR_variant	1/23	1	NM_018668.5	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1593 AN: 152188 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00331 AC: 587 AN: 177520 Hom.: 7 AF XY: 0.00284 AC XY: 271 AN XY: 95400

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000288

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00166 AC: 2330 AN: 1402814 Hom.: 21 Cov.: 30 AF XY: 0.00155 AC XY: 1072 AN XY: 690432

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000248

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000674

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.0105 AC: 1601 AN: 152306 Hom.: 19 Cov.: 32 AF XY: 0.0104 AC XY: 772 AN XY: 74482

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00633 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2020

- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.71
Cadd	Benign	16
Dann	Benign	0.90

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: rs11542639; hg19: chr15-91565487;