rs149318176

chr8-99861926-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017890.5(VPS13B):c.11270G>A(p.Arg3757Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,595,114 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3757W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (13 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: 7.48

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021757007).
• BP6: Variant 8-99861926-G-A is Benign according to our data. Variant chr8-99861926-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198013.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=9}. Variant chr8-99861926-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.11270G>A	p.Arg3757Gln	missense_variant	58/62	ENST00000358544.7
VPS13B	NM_152564.5	c.11195G>A	p.Arg3732Gln	missense_variant	58/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.11270G>A	p.Arg3757Gln	missense_variant	58/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.11195G>A	p.Arg3732Gln	missense_variant	58/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152062 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00186 AC: 396 AN: 213012 Hom.: 4 AF XY: 0.00223 AC XY: 257 AN XY: 115014

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00403

Gnomad FIN exome AF: 0.0000575

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00156 AC: 2252 AN: 1442934 Hom.: 13 Cov.: 32 AF XY: 0.00167 AC XY: 1194 AN XY: 715874

Gnomad4 AFR exome AF: 0.000541

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.000897

Gnomad4 EAS exome AF: 0.000180

Gnomad4 SAS exome AF: 0.00400

Gnomad4 FIN exome AF: 0.0000988

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152180 Hom.: 1 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74378

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00140 Hom.: 1

Bravo AF: 0.00180

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00155 AC: 187

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Uncertain:2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	VPS13B NM_017890.4 exon 58 p.Arg3757Gln (c.11270G>A): This variant has not been reported in the literature but is present in 0.4% (108/26824) of South Asian alleles, including 2 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/8-100874154-G-A). This variant is present in ClinVar (Variation ID:198013). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 19, 2021	- -

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	VPS13B: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 22, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

VPS13B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.18	T;T
Sift4G	Benign	0.072	T;T
Polyphen		1.0	D;D
Vest4		0.77
MVP		0.75
MPC		0.36
ClinPred		0.026	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149318176; hg19: chr8-100874154;