chr15-90998850-G-A

Variant names:

• chr15-90998850-G-A
• rs76401688
• NM_018668.5:c.*125C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_018668.5(VPS33B):​c.*125C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 968,658 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (18 hom.)
• Consequence: VPS33B NM_018668.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.53
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00416 (633/152290) while in subpopulation NFE AF = 0.00629 (428/68038). AF 95% confidence interval is 0.0058. There are 5 homozygotes in GnomAd4. There are 293 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.*125C>T		3_prime_UTR	Exon 23 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.*125C>T		3_prime_UTR	Exon 22 of 22	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.*125C>T		3_prime_UTR	Exon 22 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.*125C>T		3_prime_UTR	Exon 23 of 23	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1774+827C>T		intron	N/A	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.*125C>T		3_prime_UTR	Exon 23 of 23	ENSP00000523184.1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00467 AC: 3814 AN: 816368 Hom.: 18 Cov.: 11 AF XY: 0.00454 AC XY: 1925 AN XY: 424416

African (AFR) AF: 0.00147 AC: 30 AN: 20426

American (AMR) AF: 0.00298 AC: 105 AN: 35234

Ashkenazi Jewish (ASJ) AF: 0.00297 AC: 64 AN: 21566

East Asian (EAS) AF: 0.00 AC: 0 AN: 33714

South Asian (SAS) AF: 0.000887 AC: 60 AN: 67672

European-Finnish (FIN) AF: 0.00818 AC: 403 AN: 49296

Middle Eastern (MID) AF: 0.00197 AC: 9 AN: 4578

European-Non Finnish (NFE) AF: 0.00547 AC: 2979 AN: 544978

Other (OTH) AF: 0.00422 AC: 164 AN: 38904

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74452

African (AFR) AF: 0.00120 AC: 50 AN: 41550

American (AMR) AF: 0.00307 AC: 47 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00792 AC: 84 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00629 AC: 428 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00542 Hom.: 1

Bravo AF: 0.00357

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.5
DANN	Benign	0.48
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs76401688; hg19: chr15-91542080;