8-99717158-ATT-ATTTT

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_152564.5(VPS13B):​c.6455-5_6455-4dupTT 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_152564.5 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: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.6530-5_6530-4dupTT		splice_region intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.6455-5_6455-4dupTT		splice_region intron	N/A	NP_689777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.6530-13_6530-12insTT		intron	N/A	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.6455-13_6455-12insTT		intron	N/A	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.6530-13_6530-12insTT		intron	N/A	ENSP00000507923.1	A0A804HKG9

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cohen syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;