rs3826033

chr15-91005371-G-Achr15-91005371-G-C

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.1105+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,972 control chromosomes in the GnomAD database, including 21,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1983 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19723 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47

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=-0.83).
• BP6: Variant 15-91005371-G-A is Benign according to our data. Variant chr15-91005371-G-A is described in ClinVar as [Benign]. Clinvar id is 261037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-91005371-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33B	NM_018668.5	c.1105+9C>T		intron_variant		ENST00000333371.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33B	ENST00000333371.8	c.1105+9C>T		intron_variant		1	NM_018668.5	P1
VPS33B	ENST00000535906.1	c.1024+9C>T		intron_variant		2
VPS33B	ENST00000574755.5	c.*800+9C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19625 AN: 151992 Hom.: 1972 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.187 AC: 47060 AN: 251192 Hom.: 6156 AF XY: 0.183 AC XY: 24801 AN XY: 135766

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.0978

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.147 AC: 214562 AN: 1461862 Hom.: 19723 Cov.: 37 AF XY: 0.148 AC XY: 107542 AN XY: 727240

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.488

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.129 AC: 19645 AN: 152110 Hom.: 1983 Cov.: 32 AF XY: 0.135 AC XY: 10049 AN XY: 74348

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.0920

Gnomad4 EAS AF: 0.498

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.156

Alfa AF: 0.128 Hom.: 2476

Bravo AF: 0.132

Asia WGS AF: 0.352 AC: 1220 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.131

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.44
Dann	Benign	0.40
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: rs3826033; hg19: chr15-91548601; COSMIC: COSV60979066; COSMIC: COSV60979066;