15-90999107-C-T

Position:

• chr15-90999107-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018668.5(VPS33B):​c.1775-53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,573,576 control chromosomes in the GnomAD database, including 15,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2221 hom., cov: 32)
  • Exomes 𝑓: 0.10 (13084 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.647

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-90999107-C-T is Benign according to our data. Variant chr15-90999107-C-T is described in ClinVar as [Benign]. Clinvar id is 1288168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.1775-53G>A		intron_variant		ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-53G>A		intron_variant		1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.1694-53G>A		intron_variant		2
VPS33B	ENST00000574755.5	c.*1470-53G>A		intron_variant, NMD_transcript_variant		2
VPS33B	ENST00000557470.5	n.148-53G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21782 AN: 151990 Hom.: 2213 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.104 AC: 148459 AN: 1421468 Hom.: 13084 Cov.: 24 AF XY: 0.105 AC XY: 74482 AN XY: 707820

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.318

Gnomad4 ASJ exome AF: 0.0734

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.0758

Gnomad4 NFE exome AF: 0.0736

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.143 AC: 21806 AN: 152108 Hom.: 2221 Cov.: 32 AF XY: 0.148 AC XY: 10995 AN XY: 74362

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.0798

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0727

Gnomad4 NFE AF: 0.0764

Gnomad4 OTH AF: 0.149

Alfa AF: 0.113 Hom.: 719

Bravo AF: 0.162

Asia WGS AF: 0.303 AC: 1051 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.68
DANN	Benign	0.49

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: rs3743449; hg19: chr15-91542337;