rs376088912

Variant names:

• chr15-90999183-G-GC
• rs376088912
• NM_018668.5:c.1775-130dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018668.5(VPS33B):​c.1775-130dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 854,228 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 15-90999183-G-GC is Benign according to our data. Variant chr15-90999183-G-GC is described in ClinVar as Likely_benign. ClinVar VariationId is 1706786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00452 (689/152314) while in subpopulation AFR AF = 0.0155 (643/41556). AF 95% confidence interval is 0.0145. There are 11 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.1775-130dupG		intron	N/A	NP_061138.3
	VPS33B	NM_001289148.1		c.1694-130dupG		intron	N/A	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.1502-130dupG		intron	N/A	NP_001276078.1	Q9H267-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.1775-130_1775-129insG		intron	N/A	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1774+493_1774+494insG		intron	N/A	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.1790-130_1790-129insG		intron	N/A	ENSP00000523184.1

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 689 AN: 152196 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00525

GnomAD4 exome AF: 0.000672 AC: 472 AN: 701914 Hom.: 2 Cov.: 9 AF XY: 0.000546 AC XY: 202 AN XY: 369748

African (AFR) AF: 0.0165 AC: 301 AN: 18266

American (AMR) AF: 0.00184 AC: 64 AN: 34746

Ashkenazi Jewish (ASJ) AF: 0.000863 AC: 18 AN: 20862

East Asian (EAS) AF: 0.00 AC: 0 AN: 32724

South Asian (SAS) AF: 0.0000307 AC: 2 AN: 65082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44108

Middle Eastern (MID) AF: 0.00199 AC: 6 AN: 3008

European-Non Finnish (NFE) AF: 0.0000737 AC: 33 AN: 448006

Other (OTH) AF: 0.00137 AC: 48 AN: 35112

GnomAD4 genome AF: 0.00452 AC: 689 AN: 152314 Hom.: 11 Cov.: 32 AF XY: 0.00408 AC XY: 304 AN XY: 74488

African (AFR) AF: 0.0155 AC: 643 AN: 41556

American (AMR) AF: 0.00176 AC: 27 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00327 Hom.: 2

Bravo AF: 0.00521

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.015
Mutation Taster		=100/0	polymorphism

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: rs376088912; hg19: chr15-91542413;