chr15-90999107-C-T

Variant names:

• chr15-90999107-C-T
• rs3743449
• NM_018668.5:c.1775-53G>A

Variant summary

Our verdict is Benign. The variant received -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]

ENSG00000284946 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1775-53G>A		intron_variant	Intron 22 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-53G>A		intron_variant	Intron 22 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1774+570G>A		intron_variant	Intron 22 of 34			ENSP00000494429.1

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 AC: 6451 AN: 32834

Gnomad4 AMR exome AF: 0.318 AC: 13580 AN: 42756

Gnomad4 ASJ exome AF: 0.0734 AC: 1886 AN: 25706

Gnomad4 EAS exome AF: 0.499 AC: 19653 AN: 39374

Gnomad4 SAS exome AF: 0.182 AC: 15293 AN: 83968

Gnomad4 FIN exome AF: 0.0758 AC: 4002 AN: 52808

Gnomad4 NFE exome AF: 0.0736 AC: 79404 AN: 1079188

Gnomad4 Remaining exome AF: 0.123 AC: 7268 AN: 59158

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 AC: 0.190532 AN: 0.190532

Gnomad4 AMR AF: 0.255 AC: 0.255304 AN: 0.255304

Gnomad4 ASJ AF: 0.0798 AC: 0.0797811 AN: 0.0797811

Gnomad4 EAS AF: 0.471 AC: 0.470531 AN: 0.470531

Gnomad4 SAS AF: 0.194 AC: 0.194479 AN: 0.194479

Gnomad4 FIN AF: 0.0727 AC: 0.0726552 AN: 0.0726552

Gnomad4 NFE AF: 0.0764 AC: 0.0763801 AN: 0.0763801

Gnomad4 OTH AF: 0.149 AC: 0.148534 AN: 0.148534

Alfa AF: 0.107 Hom.: 1000

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs3743449; hg19: chr15-91542337;