rs111274092

Positions:

• chr15-91014444-GAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018668.5(VPS33B):​c.240-13_240-12delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0856 in 1,607,042 control chromosomes in the GnomAD database, including 5,909 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (743 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5166 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.492

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 15-91014444-GAA-G is Benign according to our data. Variant chr15-91014444-GAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 261045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-91014444-GAA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.240-13_240-12delTT		intron_variant		ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.240-13_240-12delTT		intron_variant		1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.240-13_240-12delTT		intron_variant				ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14228 AN: 151204 Hom.: 742 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0620

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0846

Gnomad OTH AF: 0.0943

GnomAD3 exomes AF: 0.0855 AC: 21280 AN: 248754 Hom.: 1053 AF XY: 0.0891 AC XY: 12007 AN XY: 134686

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0415

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0209

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.0777

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.0888

GnomAD4 exome AF: 0.0847 AC: 123336 AN: 1455720 Hom.: 5166 AF XY: 0.0863 AC XY: 62494 AN XY: 724498

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.0163

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0799

Gnomad4 NFE exome AF: 0.0829

Gnomad4 OTH exome AF: 0.0856

GnomAD4 genome AF: 0.0941 AC: 14245 AN: 151322 Hom.: 743 Cov.: 32 AF XY: 0.0938 AC XY: 6931 AN XY: 73892

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0618

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0211

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0766

Gnomad4 NFE AF: 0.0846

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.0991 Hom.: 140

Bravo AF: 0.0924

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 09, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2019	This variant is associated with the following publications: (PMID: 16896922) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Arthrogryposis with renal dysfunction and cholestasis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs111274092; hg19: chr15-91557674;