chr8-99861911-G-T

Variant names:

• chr8-99861911-G-T
• rs913075497
• NM_017890.5:c.11255G>T

Variant summary

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

The NM_152564.5(VPS13B):​c.11180G>T​(p.Arg3727Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,445,132 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3727Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.32
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.11255G>T	p.Arg3752Leu	missense	Exon 58 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11180G>T	p.Arg3727Leu	missense	Exon 58 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.11255G>T	p.Arg3752Leu	missense	Exon 58 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11180G>T	p.Arg3727Leu	missense	Exon 58 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.*349G>T		non_coding_transcript_exon	Exon 59 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717102

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.0000237 AC: 1 AN: 42248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.00 AC: 0 AN: 39040

South Asian (SAS) AF: 0.00 AC: 0 AN: 83268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104918

Other (OTH) AF: 0.00 AC: 0 AN: 59724

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.94	L
PhyloP100		6.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.26
Sift	Benign	0.35	T
Sift4G	Benign	0.063	T
Polyphen		0.66	P
Vest4		0.77
MutPred		0.50		Loss of methylation at R3752 (P = 0.012)
MVP		0.76
MPC		0.39
ClinPred		0.91	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.95
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs913075497; hg19: chr8-100874139;