rs12595616

Variant names:

• chr15-91020283-T-C
• rs12595616
• NM_018668.5:c.96+1871A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018668.5(VPS33B):​c.96+1871A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,140 control chromosomes in the GnomAD database, including 26,020 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (26020 hom., cov: 33)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.96+1871A>G		intron_variant	Intron 1 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.96+1871A>G		intron_variant	Intron 1 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.96+1871A>G		intron_variant	Intron 1 of 34			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83700 AN: 152022 Hom.: 25971 Cov.: 33

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.992

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.538

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.551 AC: 83813 AN: 152140 Hom.: 26020 Cov.: 33 AF XY: 0.558 AC XY: 41475 AN XY: 74370

African (AFR) AF: 0.777 AC: 32274 AN: 41512

American (AMR) AF: 0.621 AC: 9489 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1451 AN: 3472

East Asian (EAS) AF: 0.992 AC: 5145 AN: 5186

South Asian (SAS) AF: 0.701 AC: 3387 AN: 4832

European-Finnish (FIN) AF: 0.392 AC: 4147 AN: 10582

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26197 AN: 67968

Other (OTH) AF: 0.545 AC: 1150 AN: 2110

Alfa AF: 0.504 Hom.: 3758

Bravo AF: 0.581

Asia WGS AF: 0.850 AC: 2950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.17
DANN	Benign	0.53
PhyloP100		-1.9
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: rs12595616; hg19: chr15-91563513;