chr15-91004910-G-C

Variant names:

• chr15-91004910-G-C
• rs943813904
• NM_018668.5:c.1192C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018668.5(VPS33B):​c.1192C>G​(p.Arg398Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS33B NM_018668.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	NM_018668.5	MANE Select	c.1192C>G	p.Arg398Gly	missense	Exon 16 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.1111C>G	p.Arg371Gly	missense	Exon 15 of 22	NP_001276077.1
	VPS33B	NM_001289149.1		c.919C>G	p.Arg307Gly	missense	Exon 15 of 22	NP_001276078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.1192C>G	p.Arg398Gly	missense	Exon 16 of 23	ENSP00000327650.4
	ENSG00000284946	ENST00000643536.1		n.1192C>G		non_coding_transcript_exon	Exon 16 of 35	ENSP00000494429.1
	VPS33B	ENST00000535906.1	TSL:2	c.1111C>G	p.Arg371Gly	missense	Exon 15 of 22	ENSP00000444053.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.99
MutPred		0.84		Loss of catalytic residue at R398 (P = 0.0781)
MVP		0.91
MPC		0.75
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.78
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs943813904; hg19: chr15-91548140;