rs111274092

Variant names:

• chr15-91014444-GAA-G
• rs111274092
• NM_018668.5:c.240-13_240-12delTT

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 Benign/Likely_benign. ClinVar VariationId is 261045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018668.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.240-13_240-12delTT		intron	N/A	NP_061138.3
	VPS33B	NM_001289148.1		c.159-13_159-12delTT		intron	N/A	NP_001276077.1
	VPS33B	NM_001289149.1		c.-34-13_-34-12delTT		intron	N/A	NP_001276078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.240-13_240-12delTT		intron	N/A	ENSP00000327650.4
	ENSG00000284946	ENST00000643536.1		n.240-13_240-12delTT		intron	N/A	ENSP00000494429.1
	VPS33B	ENST00000535906.1	TSL:2	c.159-13_159-12delTT		intron	N/A	ENSP00000444053.1

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

GnomAD2 exomes AF: 0.0855 AC: 21280 AN: 248754 AF XY: 0.0891

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 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

African (AFR) AF: 0.135 AC: 4466 AN: 33090

American (AMR) AF: 0.0434 AC: 1897 AN: 43716

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2979 AN: 25986

East Asian (EAS) AF: 0.0163 AC: 646 AN: 39670

South Asian (SAS) AF: 0.132 AC: 11333 AN: 85782

European-Finnish (FIN) AF: 0.0799 AC: 4260 AN: 53284

Middle Eastern (MID) AF: 0.135 AC: 772 AN: 5732

European-Non Finnish (NFE) AF: 0.0829 AC: 91834 AN: 1108332

Other (OTH) AF: 0.0856 AC: 5149 AN: 60128

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

African (AFR) AF: 0.127 AC: 5251 AN: 41262

American (AMR) AF: 0.0618 AC: 942 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3466

East Asian (EAS) AF: 0.0211 AC: 109 AN: 5172

South Asian (SAS) AF: 0.133 AC: 636 AN: 4794

European-Finnish (FIN) AF: 0.0766 AC: 788 AN: 10284

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.0846 AC: 5737 AN: 67810

Other (OTH) AF: 0.0938 AC: 197 AN: 2100

Alfa AF: 0.0991 Hom.: 140

Bravo AF: 0.0924

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Arthrogryposis with renal dysfunction and cholestasis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111274092; hg19: chr15-91557674;