rs116746734

Variant names:

• chr8-99848776-G-A
• rs116746734
• NM_017890.5:c.10018G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-99848776-G-A
• chr8-99848776-G-T
• chr8-99848776-G-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_152564.5(VPS13B):​c.9943G>A​(p.Val3315Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00122 in 1,613,758 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3315F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (12 hom.)
• Consequence: VPS13B NM_152564.5 missense, splice_region
• Scores: Splicing: ADA: 0.9982
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.68
• Publications: 2 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 8-99848776-G-A is Benign according to our data. Variant chr8-99848776-G-A is described in ClinVar as Benign. ClinVar VariationId is 130716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00645 (981/152204) while in subpopulation AFR AF = 0.0225 (936/41508). AF 95% confidence interval is 0.0214. There are 12 homozygotes in GnomAd4. There are 475 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.10018G>A	p.Val3340Ile	missense splice_region	Exon 55 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.9943G>A	p.Val3315Ile	missense splice_region	Exon 55 of 62	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.10018G>A	p.Val3340Ile	missense splice_region	Exon 55 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.9943G>A	p.Val3315Ile	missense splice_region	Exon 55 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.10018G>A		splice_region non_coding_transcript_exon	Exon 55 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 979 AN: 152086 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00161 AC: 404 AN: 251420 AF XY: 0.00112

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000680 AC: 994 AN: 1461554 Hom.: 12 Cov.: 30 AF XY: 0.000615 AC XY: 447 AN XY: 727102

African (AFR) AF: 0.0251 AC: 841 AN: 33472

American (AMR) AF: 0.000693 AC: 31 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111726

Other (OTH) AF: 0.00116 AC: 70 AN: 60388

GnomAD4 genome AF: 0.00645 AC: 981 AN: 152204 Hom.: 12 Cov.: 32 AF XY: 0.00638 AC XY: 475 AN XY: 74400

African (AFR) AF: 0.0225 AC: 936 AN: 41508

American (AMR) AF: 0.00177 AC: 27 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00206 Hom.: 15

Bravo AF: 0.00727

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cohen syndrome (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.093
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.10
Sift	Benign	0.62	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.18
MVP		0.40
MPC		0.13
ClinPred		0.015	T
GERP RS		5.5
Varity_R		0.069
gMVP		0.14
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.10		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: rs116746734; hg19: chr8-100861004;