chr15-91007002-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018668.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.648C>T	p.Gly216Gly	synonymous	Exon 9 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.567C>T	p.Gly189Gly	synonymous	Exon 8 of 22	NP_001276077.1
	VPS33B	NM_001289149.1		c.375C>T	p.Gly125Gly	synonymous	Exon 8 of 22	NP_001276078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.648C>T	p.Gly216Gly	synonymous	Exon 9 of 23	ENSP00000327650.4
	ENSG00000284946	ENST00000643536.1		n.648C>T		non_coding_transcript_exon	Exon 9 of 35	ENSP00000494429.1
	VPS33B	ENST00000535906.1	TSL:2	c.567C>T	p.Gly189Gly	synonymous	Exon 8 of 22	ENSP00000444053.1

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

GnomAD2 exomes AF: 0.00546 AC: 1362 AN: 249226 AF XY: 0.00399

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 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

African (AFR) AF: 0.0604 AC: 2023 AN: 33480

American (AMR) AF: 0.00550 AC: 246 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00888 AC: 232 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000524 AC: 583 AN: 1112006

Other (OTH) AF: 0.00558 AC: 337 AN: 60394

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

African (AFR) AF: 0.0603 AC: 2504 AN: 41542

American (AMR) AF: 0.00766 AC: 117 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68006

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00784 Hom.: 20

Bravo AF: 0.0206

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Arthrogryposis, renal dysfunction, and cholestasis 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.4
DANN	Benign	0.55
PhyloP100		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs59648701; hg19: chr15-91550232;