rs1193250444

chr9-77314663-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033305.3(VPS13A):c.4411C>T(p.Arg1471Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: VPS13A NM_033305.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.002450
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 9-77314663-C-T is Pathogenic according to our data. Variant chr9-77314663-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 448862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.4411C>T	p.Arg1471Ter	stop_gained, splice_region_variant	37/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.4294C>T	p.Arg1432Ter	stop_gained, splice_region_variant	36/71
VPS13A	NM_015186.4	c.4411C>T	p.Arg1471Ter	stop_gained, splice_region_variant	37/69
VPS13A	NM_001018038.3	c.4411C>T	p.Arg1471Ter	stop_gained, splice_region_variant	37/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.4411C>T	p.Arg1471Ter	stop_gained, splice_region_variant	37/72	1	NM_033305.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248792 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458464 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725778

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 02, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 448862). This premature translational stop signal has been observed in individuals with chorea-acanthocytosis (PMID: 12404112, 25733999, 31192303). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg1471*) 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). -

Chorea-acanthocytosis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.90
GERP RS		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.41
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

LitVar

Other links and lift over

dbSNP: rs1193250444; hg19: chr9-79929579;