rs75904081

Positions:

• chr8-99823988-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152564.5(VPS13B):​c.9330+10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,610,672 control chromosomes in the GnomAD database, including 525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (27 hom., cov: 32)
  • Exomes 𝑓: 0.024 (498 hom.)
• Consequence: VPS13B NM_152564.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0140

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-99823988-T-A is Benign according to our data. Variant chr8-99823988-T-A is described in ClinVar as [Benign]. Clinvar id is 130728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99823988-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2192/152238) while in subpopulation NFE AF= 0.0255 (1734/68010). AF 95% confidence interval is 0.0245. There are 27 homozygotes in gnomad4. There are 996 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.9405+10T>A		intron_variant		ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.9330+10T>A		intron_variant		ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.9405+10T>A		intron_variant		1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.9330+10T>A		intron_variant		1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152120 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0139 AC: 3440 AN: 248254 Hom.: 45 AF XY: 0.0141 AC XY: 1893 AN XY: 134614

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.00794

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0243 AC: 35487 AN: 1458434 Hom.: 498 Cov.: 31 AF XY: 0.0237 AC XY: 17198 AN XY: 725712

Gnomad4 AFR exome AF: 0.00389

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.00801

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0144 AC: 2192 AN: 152238 Hom.: 27 Cov.: 32 AF XY: 0.0134 AC XY: 996 AN XY: 74426

Gnomad4 AFR AF: 0.00421

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0179 Hom.: 9

Bravo AF: 0.0144

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs75904081; hg19: chr8-100836216;