NM_017890.5:c.11119+33C>A

Variant names:

• chr8-99859513-C-A
• rs72676269
• NM_017890.5:c.11119+33C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017890.5(VPS13B):​c.11119+33C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,595,412 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (131 hom.)
• Consequence: VPS13B NM_017890.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.05
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-99859513-C-A is Benign according to our data. Variant chr8-99859513-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00788 (1185/150408) while in subpopulation NFE AF = 0.0122 (823/67558). AF 95% confidence interval is 0.0115. There are 8 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. 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
	VPS13B	NM_017890.5	MANE Plus Clinical	c.11119+33C>A		intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11044+33C>A		intron	N/A	NP_689777.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.11119+33C>A		intron	N/A	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11044+33C>A		intron	N/A	ENSP00000349685.2
	VPS13B	ENST00000682153.1		n.*213+33C>A		intron	N/A	ENSP00000507923.1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1186 AN: 150296 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00277

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.00232

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00724

GnomAD2 exomes AF: 0.00877 AC: 2016 AN: 229860 AF XY: 0.00878

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00377

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00646

GnomAD4 exome AF: 0.0118 AC: 17101 AN: 1445004 Hom.: 131 Cov.: 32 AF XY: 0.0116 AC XY: 8325 AN XY: 719376

African (AFR) AF: 0.00253 AC: 83 AN: 32868

American (AMR) AF: 0.00320 AC: 140 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 75 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00233 AC: 198 AN: 84932

European-Finnish (FIN) AF: 0.0138 AC: 649 AN: 47108

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5718

European-Non Finnish (NFE) AF: 0.0140 AC: 15445 AN: 1105286

Other (OTH) AF: 0.00852 AC: 510 AN: 59866

GnomAD4 genome AF: 0.00788 AC: 1185 AN: 150408 Hom.: 8 Cov.: 32 AF XY: 0.00771 AC XY: 566 AN XY: 73394

African (AFR) AF: 0.00276 AC: 113 AN: 40870

American (AMR) AF: 0.00418 AC: 63 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 8 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00168 AC: 8 AN: 4758

European-Finnish (FIN) AF: 0.0150 AC: 154 AN: 10270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0122 AC: 823 AN: 67558

Other (OTH) AF: 0.00716 AC: 15 AN: 2094

Alfa AF: 0.0109 Hom.: 10

Bravo AF: 0.00656

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 24, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.050
DANN	Benign	0.64
PhyloP100		-2.1
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: rs72676269; hg19: chr8-100871741;