15-91017831-G-T

Variant names:

• chr15-91017831-G-T
• rs11542638
• NM_018668.5:c.151C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018668.5(VPS33B):​c.151C>A​(p.Arg51Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.0866 in 1,613,564 control chromosomes in the GnomAD database, including 6,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R51R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.094 (766 hom., cov: 30)
  • Exomes 𝑓: 0.086 (5977 hom.)
• Consequence: VPS33B NM_018668.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.93
• Publications: 18 publications found

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]

ENSG00000284946 (HGNC:):

VPS33B-DT (HGNC:51413): (VPS33B divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-91017831-G-T is Benign according to our data. Variant chr15-91017831-G-T is described in ClinVar as Benign. ClinVar VariationId is 261040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.151C>A	p.Arg51Arg	synonymous_variant	Exon 2 of 23	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.151C>A	p.Arg51Arg	synonymous_variant	Exon 2 of 23	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.151C>A		non_coding_transcript_exon_variant	Exon 2 of 35			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14295 AN: 152046 Hom.: 765 Cov.: 30

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0751

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.0926

GnomAD2 exomes AF: 0.0852 AC: 21415 AN: 251456 AF XY: 0.0889

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0204

Gnomad FIN exome AF: 0.0783

Gnomad NFE exome AF: 0.0898

Gnomad OTH exome AF: 0.0877

GnomAD4 exome AF: 0.0858 AC: 125436 AN: 1461400 Hom.: 5977 Cov.: 31 AF XY: 0.0873 AC XY: 63475 AN XY: 727032

African (AFR) AF: 0.137 AC: 4573 AN: 33474

American (AMR) AF: 0.0420 AC: 1880 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3031 AN: 26132

East Asian (EAS) AF: 0.0164 AC: 650 AN: 39698

South Asian (SAS) AF: 0.133 AC: 11500 AN: 86248

European-Finnish (FIN) AF: 0.0805 AC: 4298 AN: 53388

Middle Eastern (MID) AF: 0.128 AC: 735 AN: 5764

European-Non Finnish (NFE) AF: 0.0842 AC: 93541 AN: 1111598

Other (OTH) AF: 0.0866 AC: 5228 AN: 60376

GnomAD4 genome AF: 0.0941 AC: 14312 AN: 152164 Hom.: 766 Cov.: 30 AF XY: 0.0936 AC XY: 6966 AN XY: 74402

African (AFR) AF: 0.128 AC: 5308 AN: 41516

American (AMR) AF: 0.0610 AC: 931 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3472

East Asian (EAS) AF: 0.0212 AC: 110 AN: 5178

South Asian (SAS) AF: 0.133 AC: 640 AN: 4816

European-Finnish (FIN) AF: 0.0751 AC: 797 AN: 10606

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0845 AC: 5743 AN: 67986

Other (OTH) AF: 0.0922 AC: 195 AN: 2116

Alfa AF: 0.0818 Hom.: 405

Bravo AF: 0.0926

Asia WGS AF: 0.0670 AC: 231 AN: 3478

EpiCase AF: 0.0890

EpiControl AF: 0.0848

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.42
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.090		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: rs11542638; hg19: chr15-91561061; COSMIC: COSV108139379; COSMIC: COSV108139379;