9-77177781-A-AG

Variant summary

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

The NM_033305.3(VPS13A):c.78dup(p.Leu27AlafsTer18) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS13A NM_033305.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.32

Genes affected

VPS13A (HGNC:1908): (vacuolar protein sorting 13 homolog A) The protein encoded by this gene may control steps in the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. Mutations in this gene cause the autosomal recessive disorder, chorea-acanthocytosis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

VPS13A-AS1 (HGNC:44167): (VPS13A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 166 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-77177781-A-AG is Pathogenic according to our data. Variant chr9-77177781-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 1076960.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.78dup	p.Leu27AlafsTer18	frameshift_variant	1/72	ENST00000360280.8
VPS13A-AS1	NR_026668.2	n.136_137insC		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.78dup	p.Leu27AlafsTer18	frameshift_variant	1/72	1	NM_033305.3	P4
VPS13A-AS1	ENST00000644612.1	n.399_400insC		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 05, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in VPS13A are known to be pathogenic (PMID: 12404112, 21598378). This variant has not been reported in the literature in individuals with VPS13A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu27Alafs*18) in the VPS13A gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-79792697;