chr15-90998850-G-A

Position:

• chr15-90998850-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_018668.5(VPS33B):​c.*125C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 968,658 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (18 hom.)
• Consequence: VPS33B NM_018668.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.53

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00416 (633/152290) while in subpopulation NFE AF= 0.00629 (428/68038). AF 95% confidence interval is 0.0058. There are 5 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.*125C>T		3_prime_UTR_variant	23/23	ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.*125C>T		3_prime_UTR_variant	23/23	1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.*125C>T		3_prime_UTR_variant	22/22	2
VPS33B	ENST00000557470.5	n.352C>T		non_coding_transcript_exon_variant	3/3	5
VPS33B	ENST00000574755.5	c.*1674C>T		3_prime_UTR_variant, NMD_transcript_variant	22/22	2

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00467 AC: 3814 AN: 816368 Hom.: 18 Cov.: 11 AF XY: 0.00454 AC XY: 1925 AN XY: 424416

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.00297

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000887

Gnomad4 FIN exome AF: 0.00818

Gnomad4 NFE exome AF: 0.00547

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74452

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00485 Hom.: 1

Bravo AF: 0.00357

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.5
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs76401688; hg19: chr15-91542080;