chr15-91004872-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_018668.5(VPS33B):c.1225+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000342 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

VPS33B
NM_018668.5 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.88

Variant links:

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]

VPS33B links:

ENSG00000284946 (HGNC:):

ENSG00000284946 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-91004872-C-G is Pathogenic according to our data. Variant chr15-91004872-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-91004872-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5 link	c.1225+5G>C		splice_region_variant, intron_variant	Intron 16 of 22	ENST00000333371.8	NP_061138.3	Q9H267-1A0A0S2Z577

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8 link	c.1225+5G>C		splice_region_variant, intron_variant	Intron 16 of 22	1	NM_018668.5	ENSP00000327650.4		Q9H267-1
ENSG00000284946	ENST00000643536.1 link	n.1225+5G>C		splice_region_variant, intron_variant	Intron 16 of 34			ENSP00000494429.1		A0A2R8YDQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251450

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Aug 02, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate a damaging effect: shortened protein length (PMID: 22753090); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33029437, 22753090, 26505894, 31589614, 31343487, 31463586, 29907094, 31240160) -

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 16 of the VPS33B gene. It does not directly change the encoded amino acid sequence of the VPS33B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs398122407, gnomAD 0.01%). This variant has been observed in individual(s) with VPS33B-related conditions (PMID: 22753090, 26505894, 29907094, 31343487). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 88858). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Sep 22, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, renal dysfunction, and cholestasis 1

Pathogenic:2

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

VPS33B-related disorder

Pathogenic:1

Jul 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VPS33B c.1225+5G>C variant is predicted to interfere with splicing. This variant has been reported to be pathogenic for a mild arthrogryposis-renal dysfunction-cholestasis (ARC) phenotype (Smith et al. 2012. PubMed ID: 22753090; Rosales et al. 2018. PubMed ID: 29907094). A functional study showed that this splicing variant results in a truncated protein with partially reduced activity (Smith et al. 2012. PubMed ID: 22753090). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/88858). Given all the evidence, we interpret c.1225+5G>C as pathogenic. -

Arthrogryposis, renal dysfunction, and cholestasis 1;C5774200:Keratoderma-ichthyosis-deafness syndrome, autosomal recessive;C5774311:Cholestasis, progressive familial intrahepatic, 12

Pathogenic:1

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Oct 25, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1225+5G>C intronic alteration results from a G to C substitution 5 nucleotides after coding exon 16 of the VPS33B gene. Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/251450) total alleles studied. The highest observed frequency was 0.012% (4/34590) of Latino alleles. This variant has been identified in conjunction with other VPS33B variants in individuals reported to have an attenuated clinical presentation including developmental delay, sensorineural hearing loss, renal dysfunction, nephrotic syndrome, knee contractures, rocker bottom feet, cholestasis, mild arthrogryposis, and other clinical features consistent with VPS33B-related arthrogryposis, renal dysfunction, and cholestasis syndrome; in at least one instance, the variants were identified in trans (Smith, 2012; Weyand, 2016; Rosales, 2018; Agawu, 2019; Duong, 2020). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.88

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over