NM_017890.5:c.6530-5_6530-4dupTT

Variant names:

• chr8-99717158-A-ATT
• rs398124337
• NM_017890.5:c.6530-5_6530-4dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_017890.5(VPS13B):​c.6530-5_6530-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,422,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: VPS13B NM_017890.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.735
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 8-99717158-A-ATT is Benign according to our data. Variant chr8-99717158-A-ATT is described in ClinVar as Benign. ClinVar VariationId is 2851418.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.6530-5_6530-4dupTT		splice_region_variant, intron_variant	Intron 36 of 61	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.6455-5_6455-4dupTT		splice_region_variant, intron_variant	Intron 36 of 61	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.6530-5_6530-4dupTT		splice_region_variant, intron_variant	Intron 36 of 61	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.6455-5_6455-4dupTT		splice_region_variant, intron_variant	Intron 36 of 61	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1422932 Hom.: 0 Cov.: 30 AF XY: 0.00000423 AC XY: 3 AN XY: 709162

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32506

American (AMR) AF: 0.00 AC: 0 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39018

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079054

Other (OTH) AF: 0.0000170 AC: 1 AN: 58918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cohen syndrome Benign:1

Apr 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.73

Splicing

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

Other links and lift over

dbSNP: rs398124337; hg19: chr8-100729386;