chr15-90999183-G-GC

Position:

• chr15-90999183-G-GC

Variant summary

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

The NM_018668.5(VPS33B):​c.1775-130_1775-129insG 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

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 15-90999183-G-GC is Benign according to our data. Variant chr15-90999183-G-GC is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.1775-130_1775-129insG		intron_variant		ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-130_1775-129insG		intron_variant		1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.1694-130_1694-129insG		intron_variant		2
VPS33B	ENST00000574755.5	c.*1470-130_*1470-129insG		intron_variant, NMD_transcript_variant		2
VPS33B	ENST00000557470.5	n.148-130_148-129insG		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.000863

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000307

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.00137

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

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000576

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

See Variant Classification Assertion Criteria. -

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: rs376088912; hg19: chr15-91542413;