chr15-91002014-C-T

Variant names:

• chr15-91002014-C-T
• rs116787959
• NM_018668.5:c.1405+36G>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.1405+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,612,852 control chromosomes in the GnomAD database, including 500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (253 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (247 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.54

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=-0.87).
• BP6: Variant 15-91002014-C-T is Benign according to our data. Variant chr15-91002014-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1405+36G>A		intron_variant	Intron 18 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1405+36G>A		intron_variant	Intron 18 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1405+36G>A		intron_variant	Intron 18 of 34			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4700 AN: 152184 Hom.: 249 Cov.: 31

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00858 AC: 2157 AN: 251334 AF XY: 0.00639

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00353 AC: 5151 AN: 1460550 Hom.: 247 Cov.: 32 AF XY: 0.00317 AC XY: 2302 AN XY: 726576

African (AFR) AF: 0.112 AC: 3750 AN: 33436

American (AMR) AF: 0.00579 AC: 259 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00352 AC: 303 AN: 86178

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53372

Middle Eastern (MID) AF: 0.00700 AC: 34 AN: 4858

European-Non Finnish (NFE) AF: 0.000256 AC: 285 AN: 1111882

Other (OTH) AF: 0.00796 AC: 480 AN: 60292

GnomAD4 genome AF: 0.0310 AC: 4725 AN: 152302 Hom.: 253 Cov.: 31 AF XY: 0.0305 AC XY: 2269 AN XY: 74462

African (AFR) AF: 0.106 AC: 4420 AN: 41562

American (AMR) AF: 0.0124 AC: 190 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68024

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.00565 Hom.: 3

Bravo AF: 0.0357

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.43
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs116787959; hg19: chr15-91545244;