9-77177775-C-CG

Variant summary

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

The NM_033305.3(VPS13A):c.72dup(p.Ser25ValfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T24T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS13A NM_033305.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0630

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 167 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-77177775-C-CG is Pathogenic according to our data. Variant chr9-77177775-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 1075838.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.72dup	p.Ser25ValfsTer20	frameshift_variant	1/72	ENST00000360280.8
VPS13A-AS1	NR_026668.2	n.142_143insC		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.72dup	p.Ser25ValfsTer20	frameshift_variant	1/72	1	NM_033305.3	P4
VPS13A-AS1	ENST00000644612.1	n.405_406insC		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

Feb 09, 2022

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1075838). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ser25Valfs*20) in the VPS13A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13A are known to be pathogenic (PMID: 12404112, 21598378). -

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: chr9-79792691;