chr8-99013347-T-A

Variant names:

• chr8-99013347-T-A
• rs886062533
• NM_017890.5:c.-30T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152564.5(VPS13B):​c.-30T>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 274,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: VPS13B NM_152564.5 splice_region
• Scores: Splicing: ADA: 0.00007008
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119
• 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-DT (HGNC:54375): (VPS13B divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

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.-30T>A		splice_region	Exon 1 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.-30T>A		splice_region	Exon 1 of 62	NP_689777.3
	VPS13B	NM_017890.5	MANE Plus Clinical	c.-30T>A		5_prime_UTR	Exon 1 of 62	NP_060360.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.-30T>A		splice_region	Exon 1 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.-30T>A		splice_region	Exon 1 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000441350.2	TSL:1	c.-30T>A		splice_region	Exon 1 of 8	ENSP00000398472.2	Q7Z7G8-5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000572 AC: 7 AN: 122318 Hom.: 0 Cov.: 0 AF XY: 0.0000604 AC XY: 4 AN XY: 66252

African (AFR) AF: 0.00 AC: 0 AN: 3854

American (AMR) AF: 0.00 AC: 0 AN: 4596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2794

East Asian (EAS) AF: 0.00 AC: 0 AN: 5322

South Asian (SAS) AF: 0.00 AC: 0 AN: 21622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 444

European-Non Finnish (NFE) AF: 0.0000976 AC: 7 AN: 71734

Other (OTH) AF: 0.00 AC: 0 AN: 6104

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151910 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74192

African (AFR) AF: 0.0000242 AC: 1 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		0.12
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: -4

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

Other links and lift over

dbSNP: rs886062533; hg19: chr8-100025575;