8-99717158-ATT-AT

Variant names:

• chr8-99717158-AT-A
• rs398124337
• NM_017890.5:c.6530-4delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_152564.5(VPS13B):​c.6455-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,573,484 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 8-99717158-AT-A is Benign according to our data. Variant chr8-99717158-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1535027.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.6530-4delT		splice_region intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.6455-4delT		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.6530-12delT		intron	N/A	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.6455-12delT		intron	N/A	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.6530-12delT		intron	N/A	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151326 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000748 AC: 17 AN: 227226 AF XY: 0.0000732

Gnomad AFR exome AF: 0.0000685

Gnomad AMR exome AF: 0.0000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000423

Gnomad FIN exome AF: 0.0000492

Gnomad NFE exome AF: 0.0000296

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.0000795 AC: 113 AN: 1422040 Hom.: 0 Cov.: 30 AF XY: 0.0000790 AC XY: 56 AN XY: 708722

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

African (AFR) AF: 0.0000923 AC: 3 AN: 32486

American (AMR) AF: 0.0000453 AC: 2 AN: 44122

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25604

East Asian (EAS) AF: 0.000205 AC: 8 AN: 39008

South Asian (SAS) AF: 0.0000469 AC: 4 AN: 85216

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.0000816 AC: 88 AN: 1078294

Other (OTH) AF: 0.000102 AC: 6 AN: 58886

⚠️ 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 AF: 0.0000396 AC: 6 AN: 151444 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 74002

African (AFR) AF: 0.0000242 AC: 1 AN: 41296

American (AMR) AF: 0.0000660 AC: 1 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67754

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs398124337; hg19: chr8-100729386;