rs386834072

Variant names:

• chr8-99134691-AGTATT-A
• rs386834072
• NM_017890.5:c.1269_1273delATTGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152564.5(VPS13B):​c.1269_1273delATTGT​(p.Cys425GlyfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,458,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS13B NM_152564.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.19

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-99134691-AGTATT-A is Pathogenic according to our data. Variant chr8-99134691-AGTATT-A is described in ClinVar as [Pathogenic]. Clinvar id is 56647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-99134691-AGTATT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift_variant	Exon 9 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift_variant	Exon 9 of 62	ENST00000357162.7	NP_689777.3
VPS13B	NM_015243.3	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift_variant	Exon 9 of 18		NP_056058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift_variant	Exon 9 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.1269_1273delATTGT	p.Cys425GlyfsTer8	frameshift_variant	Exon 9 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458250 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 19006247) -

Cohen syndrome Pathogenic:1

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs386834072; hg19: chr8-100146919;