8-99875420-A-AGAT

Position:

chr8-99875420-A-AGAT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM4_SupportingPP3BP6

The NM_017890.5(VPS13B):c.11825_11827dup(p.Asp3942dup) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

VPS13B
NM_017890.5 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: 9.28

Variant links:

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 links:

COX6C (HGNC:2285): (cytochrome c oxidase subunit 6C) Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIc, which has 77% amino acid sequence identity with mouse subunit VIc. This gene is up-regulated in prostate cancer cells. A pseudogene has been found on chromosomes 16p12. [provided by RefSeq, Jul 2010]

COX6C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_017890.5. Strenght limited to Supporting due to length of the change: 1aa.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 8-99875420-A-AGAT is Benign according to our data. Variant chr8-99875420-A-AGAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56642.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5 linkuse as main transcript	c.11825_11827dup	p.Asp3942dup	inframe_insertion	62/62	ENST00000358544.7
VPS13B	NM_152564.5 linkuse as main transcript	c.11750_11752dup	p.Asp3917dup	inframe_insertion	62/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7 linkuse as main transcript	c.11750_11752dup	p.Asp3917dup	inframe_insertion	62/62	1	NM_152564.5	P1	Q7Z7G8-2
VPS13B	ENST00000358544.7 linkuse as main transcript	c.11825_11827dup	p.Asp3942dup	inframe_insertion	62/62	1	NM_017890.5		Q7Z7G8-1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000387

AC:

AN:

250636

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000230

AC:

336

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

166

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.00142

AC:

216

AN:

152320

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00447

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.00155

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cohen syndrome

Pathogenic:1Uncertain:3Benign:1

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Sep 17, 2021	VPS13B NM_017890.4 exon 62 p.Asp3942_dup (c.11825_11827dupATG): This variant has been reported in the literature as a compound heterozygote (in trans with a multi-exon deletion of this gene) in 1 individual with a diagnosis of Cohen syndrome (Rivera-Brugues 2011 PMID:20921020, gene identified as alternate name COH1). However, this variant is present in 0.4% (100/24024) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs558633643). This variant is present in ClinVar (Variation ID:56642). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a duplication of 1 amino acid at position 3942 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 06, 2019	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	In-frame insertion of one amino acid in a non-repeat region; Reported previously using alternate nomenclature (c.1827_11828insATG) in an individual with developmental delay, cardiac defects, and dysmorphic features who harbored a partial gene deletion on the opposite allele (in trans) (Rivera-Brugues et al., 2011); This variant is associated with the following publications: (PMID: 20921020) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2018

The c.11825_11827dupATG variant (also known as p.D3942dup), located in coding exon 61 of the VPS13B gene, results from an in-frame duplication of ATG at nucleotide positions 11825 to 11827. This results in the duplication of an aspartate residue between codons 3942 and 3943. This duplication (reported as p.D3942_G3943insD) was detected in compound heterozygous state with a gross deletion encompassing exons 1 to 17 of VPS13B and exon 4 of ORS2 in a patient with developmental delay and cardiac defect (Rivera-Brugués N et al. J. Med. Genet., 2011 Feb;48:136-40). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by PROVEAN in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

VPS13B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over