chr15-90999565-C-T

Variant names:

• chr15-90999565-C-T
• rs147817266
• NM_018668.5:c.1774+112G>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.1774+112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0404 in 1,125,820 control chromosomes in the GnomAD database, including 1,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (103 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1138 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77
• Publications: 2 publications found

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:):

VPS33B-DT (HGNC:51413): (VPS33B divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 15-90999565-C-T is Benign according to our data. Variant chr15-90999565-C-T is described in ClinVar as [Benign]. Clinvar id is 1247061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1774+112G>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.1774+112G>A		intron_variant	Intron 22 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1774+112G>A		intron_variant	Intron 22 of 34			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4741 AN: 152058 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.00703

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0418 AC: 40742 AN: 973644 Hom.: 1138 Cov.: 13 AF XY: 0.0439 AC XY: 22156 AN XY: 504348

African (AFR) AF: 0.00609 AC: 147 AN: 24136

American (AMR) AF: 0.00833 AC: 365 AN: 43824

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 349 AN: 22994

East Asian (EAS) AF: 0.000728 AC: 27 AN: 37102

South Asian (SAS) AF: 0.0866 AC: 6568 AN: 75854

European-Finnish (FIN) AF: 0.0714 AC: 3090 AN: 43280

Middle Eastern (MID) AF: 0.0156 AC: 52 AN: 3332

European-Non Finnish (NFE) AF: 0.0421 AC: 28600 AN: 679024

Other (OTH) AF: 0.0350 AC: 1544 AN: 44098

GnomAD4 genome AF: 0.0312 AC: 4743 AN: 152176 Hom.: 103 Cov.: 32 AF XY: 0.0335 AC XY: 2493 AN XY: 74380

African (AFR) AF: 0.00701 AC: 291 AN: 41526

American (AMR) AF: 0.0103 AC: 157 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0864 AC: 416 AN: 4814

European-Finnish (FIN) AF: 0.0775 AC: 820 AN: 10584

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0424 AC: 2885 AN: 68000

Other (OTH) AF: 0.0123 AC: 26 AN: 2108

Alfa AF: 0.0381 Hom.: 21

Bravo AF: 0.0237

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 24, 2020

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	-1.0
CADD	Benign	0.013
DANN	Benign	0.60
PhyloP100		-2.8
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

Other links and lift over

dbSNP: rs147817266; hg19: chr15-91542795;