chr15-90999107-C-T

Variant names:

• chr15-90999107-C-T
• rs3743449
• NM_018668.5:c.1775-53G>A

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.1775-53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,573,576 control chromosomes in the GnomAD database, including 15,305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2221 hom., cov: 32)
  • Exomes 𝑓: 0.10 (13084 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.647
• Publications: 6 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=-0.85).
• BP6: Variant 15-90999107-C-T is Benign according to our data. Variant chr15-90999107-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 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.1775-53G>A		intron	N/A	NP_061138.3
	VPS33B	NM_001289148.1		c.1694-53G>A		intron	N/A	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.1502-53G>A		intron	N/A	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.1775-53G>A		intron	N/A	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1774+570G>A		intron	N/A	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.1790-53G>A		intron	N/A	ENSP00000523184.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21782 AN: 151990 Hom.: 2213 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.104 AC: 148459 AN: 1421468 Hom.: 13084 Cov.: 24 AF XY: 0.105 AC XY: 74482 AN XY: 707820

African (AFR) AF: 0.196 AC: 6451 AN: 32834

American (AMR) AF: 0.318 AC: 13580 AN: 42756

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 1886 AN: 25706

East Asian (EAS) AF: 0.499 AC: 19653 AN: 39374

South Asian (SAS) AF: 0.182 AC: 15293 AN: 83968

European-Finnish (FIN) AF: 0.0758 AC: 4002 AN: 52808

Middle Eastern (MID) AF: 0.162 AC: 922 AN: 5676

European-Non Finnish (NFE) AF: 0.0736 AC: 79404 AN: 1079188

Other (OTH) AF: 0.123 AC: 7268 AN: 59158

GnomAD4 genome AF: 0.143 AC: 21806 AN: 152108 Hom.: 2221 Cov.: 32 AF XY: 0.148 AC XY: 10995 AN XY: 74362

African (AFR) AF: 0.191 AC: 7901 AN: 41468

American (AMR) AF: 0.255 AC: 3899 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3472

East Asian (EAS) AF: 0.471 AC: 2427 AN: 5158

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.0727 AC: 770 AN: 10598

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0764 AC: 5194 AN: 68002

Other (OTH) AF: 0.149 AC: 314 AN: 2114

Alfa AF: 0.107 Hom.: 1000

Bravo AF: 0.162

Asia WGS AF: 0.303 AC: 1051 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.68
DANN	Benign	0.49
PhyloP100		-0.65
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: rs3743449; hg19: chr15-91542337;