15-90999188-GC-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018668.5(VPS33B):c.1775-135del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 819,282 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: 0.00071 (2 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.951

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 -10 ACMG points.

• BP6: Variant 15-90999188-GC-G is Benign according to our data. Variant chr15-90999188-GC-G is described in ClinVar as [Likely_benign]. Clinvar id is 1194057.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00453 (690/152316) while in subpopulation AFR AF= 0.0155 (644/41554). AF 95% confidence interval is 0.0145. There are 11 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.1775-135del		intron_variant		ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-135del		intron_variant		1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.1694-135del		intron_variant		2
VPS33B	ENST00000574755.5	c.*1470-135del		intron_variant, NMD_transcript_variant		2
VPS33B	ENST00000557470.5	n.148-135del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 690 AN: 152198 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000577

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: 0.000712 AC: 475 AN: 666966 Hom.: 2 Cov.: 8 AF XY: 0.000578 AC XY: 204 AN XY: 352786

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.000876

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000311

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000814

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00453 AC: 690 AN: 152316 Hom.: 11 Cov.: 32 AF XY: 0.00409 AC XY: 305 AN XY: 74488

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00327 Hom.: 2

Bravo AF: 0.00521

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369038329; hg19: chr15-91542418;