rs146758743

Variant names:

• chr15-91013804-C-T
• rs146758743
• NM_018668.5:c.357G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-91013804-C-T
• chr15-91013804-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_018668.5(VPS33B):​c.357G>A​(p.Lys119Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00127 in 1,614,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: VPS33B NM_018668.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.00
• Publications: 4 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 15-91013804-C-T is Benign according to our data. Variant chr15-91013804-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00119 (182/152304) while in subpopulation AMR AF = 0.00516 (79/15300). AF 95% confidence interval is 0.00425. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.357G>A	p.Lys119Lys	splice_region synonymous	Exon 5 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.276G>A	p.Lys92Lys	splice_region synonymous	Exon 4 of 22	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.84G>A	p.Lys28Lys	splice_region synonymous	Exon 4 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.357G>A	p.Lys119Lys	splice_region synonymous	Exon 5 of 23	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.357G>A		splice_region non_coding_transcript_exon	Exon 5 of 35	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.357G>A	p.Lys119Lys	splice_region synonymous	Exon 5 of 23	ENSP00000523184.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00206 AC: 518 AN: 251488 AF XY: 0.00173

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00128 AC: 1870 AN: 1461858 Hom.: 5 Cov.: 31 AF XY: 0.00116 AC XY: 847 AN XY: 727234

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00825 AC: 369 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53408

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00123 AC: 1369 AN: 1111990

Other (OTH) AF: 0.00136 AC: 82 AN: 60394

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74478

African (AFR) AF: 0.000192 AC: 8 AN: 41570

American (AMR) AF: 0.00516 AC: 79 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68032

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

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00216

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.090
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		6.0
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.11		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: rs146758743; hg19: chr15-91557034;