rs59648701

Variant names:

• chr15-91007002-G-A
• rs59648701
• NM_018668.5:c.648C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018668.5(VPS33B):​c.648C>T​(p.Gly216Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,718 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (83 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (73 hom.)
• Consequence: VPS33B NM_018668.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.223

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 15-91007002-G-A is Benign according to our data. Variant chr15-91007002-G-A is described in ClinVar as [Benign]. Clinvar id is 261047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.223 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.648C>T	p.Gly216Gly	synonymous_variant	Exon 9 of 23	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.648C>T	p.Gly216Gly	synonymous_variant	Exon 9 of 23	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.648C>T		non_coding_transcript_exon_variant	Exon 9 of 35			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2735 AN: 152078 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.0605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00546 AC: 1362 AN: 249226 Hom.: 30 AF XY: 0.00399 AC XY: 538 AN XY: 134910

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00900

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00236 AC: 3453 AN: 1461522 Hom.: 73 Cov.: 32 AF XY: 0.00206 AC XY: 1500 AN XY: 727034

Gnomad4 AFR exome AF: 0.0604

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00888

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000524

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.0180 AC: 2734 AN: 152196 Hom.: 83 Cov.: 33 AF XY: 0.0176 AC XY: 1308 AN XY: 74398

Gnomad4 AFR AF: 0.0603

Gnomad4 AMR AF: 0.00766

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00759 Hom.: 12

Bravo AF: 0.0206

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 24, 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

- -

Jan 11, 2020

GeneDx

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

- -

Arthrogryposis, renal dysfunction, and cholestasis 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.4
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs59648701; hg19: chr15-91550232;