rs150941426

Variant names:

• chr8-99103100-G-A
• rs150941426
• NM_017890.5:c.560G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152564.5(VPS13B):​c.560G>A​(p.Arg187His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27797985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.560G>A	p.Arg187His	missense_variant	Exon 5 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.560G>A	p.Arg187His	missense_variant	Exon 5 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.560G>A	p.Arg187His	missense_variant	Exon 5 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.560G>A	p.Arg187His	missense_variant	Exon 5 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251342 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135838

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Uncertain:2

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 187 of the VPS13B protein (p.Arg187His). This variant is present in population databases (rs150941426, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 437253). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS13B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 15, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Dec 28, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.560G>A (p.R187H) alteration is located in exon 5 (coding exon 4) of the VPS13B gene. This alteration results from a G to A substitution at nucleotide position 560, causing the arginine (R) at amino acid position 187 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

May 17, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R187H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R187H variant is observed in 13/30782 (0.04%) alleles from individuals of South Asian background (Lek et al., 2016). The R187H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

VPS13B-related disorder Uncertain:1

Mar 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VPS13B c.560G>A variant is predicted to result in the amino acid substitution p.Arg187His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.14	.;.;T;.
Eigen	Benign	0.026
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Benign	1.8	L;L;L;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N;N;N;D
REVEL	Uncertain	0.44
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.68	P;D;B;B
Vest4		0.72
MVP		0.74
MPC		0.54
ClinPred		0.30	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs150941426; hg19: chr8-100115328;