NM_018668.5:c.1105+9C>T

Variant names:

• chr15-91005371-G-A
• rs3826033
• NM_018668.5:c.1105+9C>T

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.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:6
• Conservation: PhyloP100: -1.47
• Publications: 38 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=-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 VariationId is 261037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1105+9C>T		intron_variant	Intron 14 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1105+9C>T		intron_variant	Intron 14 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1105+9C>T		intron_variant	Intron 14 of 34			ENSP00000494429.1

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

GnomAD2 exomes AF: 0.187 AC: 47060 AN: 251192 AF XY: 0.183

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 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

African (AFR) AF: 0.0242 AC: 809 AN: 33480

American (AMR) AF: 0.299 AC: 13377 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2622 AN: 26136

East Asian (EAS) AF: 0.488 AC: 19365 AN: 39700

South Asian (SAS) AF: 0.202 AC: 17412 AN: 86252

European-Finnish (FIN) AF: 0.152 AC: 8124 AN: 53418

Middle Eastern (MID) AF: 0.127 AC: 732 AN: 5766

European-Non Finnish (NFE) AF: 0.129 AC: 142921 AN: 1111992

Other (OTH) AF: 0.152 AC: 9200 AN: 60396

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

African (AFR) AF: 0.0307 AC: 1273 AN: 41510

American (AMR) AF: 0.220 AC: 3365 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 319 AN: 3468

East Asian (EAS) AF: 0.498 AC: 2565 AN: 5150

South Asian (SAS) AF: 0.206 AC: 994 AN: 4822

European-Finnish (FIN) AF: 0.156 AC: 1646 AN: 10574

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9023 AN: 68002

Other (OTH) AF: 0.156 AC: 328 AN: 2108

Alfa AF: 0.128 Hom.: 3271

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.83
CADD	Benign	0.44
DANN	Benign	0.40
PhyloP100		-1.5
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

Other links and lift over

dbSNP: rs3826033; hg19: chr15-91548601; COSMIC: COSV60979066; COSMIC: COSV60979066;