8-99875420-A-AGAT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM4_Supporting PP3 BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:3
• Conservation: PhyloP100: 9.28

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]

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]

ACMG classification

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: {Uncertain_significance=5, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.11825_11827dup	p.Asp3942dup	inframe_insertion	62/62	ENST00000358544.7
VPS13B	NM_152564.5	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	c.11750_11752dup	p.Asp3917dup	inframe_insertion	62/62	1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.11825_11827dup	p.Asp3942dup	inframe_insertion	62/62	1	NM_017890.5

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152202 Hom.: 0 Cov.: 32

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: 97 AN: 250636 Hom.: 1 AF XY: 0.000339 AC XY: 46 AN XY: 135560

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.: 1 Cov.: 31 AF XY: 0.000228 AC XY: 166 AN XY: 727242

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.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74502

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.: 0

Bravo AF: 0.00155

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Pathogenic:1 Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
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	Revvity Omics, Revvity	Aug 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Uncertain:1 Benign: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, criteria provided, single submitter

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386834068; hg19: chr8-100887648;