rs148071246

Variant names:

• chr15-90999780-T-C
• rs148071246
• NM_018668.5:c.1671A>G

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.1671A>G​(p.Glu557Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,112 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (290 hom.)
• Consequence: VPS33B NM_018668.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.02
• 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=-0.67).
• BP6: Variant 15-90999780-T-C is Benign according to our data. Variant chr15-90999780-T-C is described in ClinVar as Benign. ClinVar VariationId is 261044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0605 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.1671A>G	p.Glu557Glu	synonymous	Exon 22 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.1590A>G	p.Glu530Glu	synonymous	Exon 21 of 22	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.1398A>G	p.Glu466Glu	synonymous	Exon 21 of 22	NP_001276078.1	Q9H267-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.1671A>G	p.Glu557Glu	synonymous	Exon 22 of 23	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1671A>G		non_coding_transcript_exon	Exon 22 of 35	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.1686A>G	p.Glu562Glu	synonymous	Exon 22 of 23	ENSP00000523184.1

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1078 AN: 152104 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0150 AC: 3767 AN: 251490 AF XY: 0.0111

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00339 AC: 4962 AN: 1461890 Hom.: 290 Cov.: 32 AF XY: 0.00291 AC XY: 2114 AN XY: 727248

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.101 AC: 4498 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86256

European-Finnish (FIN) AF: 0.000693 AC: 37 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1112010

Other (OTH) AF: 0.00326 AC: 197 AN: 60396

GnomAD4 genome AF: 0.00708 AC: 1078 AN: 152222 Hom.: 51 Cov.: 32 AF XY: 0.00798 AC XY: 594 AN XY: 74428

African (AFR) AF: 0.00128 AC: 53 AN: 41528

American (AMR) AF: 0.0638 AC: 975 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68008

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00180 Hom.: 7

Bravo AF: 0.0121

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Arthrogryposis, renal dysfunction, and cholestasis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.0
DANN	Benign	0.68
PhyloP100		-1.0
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: rs148071246; hg19: chr15-91543010;