9-77177705-A-T

Position:

• chr9-77177705-A-T

Variant summary

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

The NM_033305.3(VPS13A):​c.1A>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS13A NM_033305.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.61

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: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-77177705-A-T is Pathogenic according to our data. Variant chr9-77177705-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1698814.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.1A>T	p.Met1?	start_lost	1/72	ENST00000360280.8
VPS13A-AS1	NR_026668.2	n.213T>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.1A>T	p.Met1?	start_lost	1/72	1	NM_033305.3	P4
VPS13A-AS1	ENST00000644612.1	n.476T>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chorea-acanthocytosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Feb 07, 2022

The VPS13A:c.1A>T variant is classified as LIKELY PATHOGENIC (PVS1_Moderate, PM2, PP4, PM3_Supporting). The VPS13A:c.1A>T variant is a single nucleotide substitution in exon 1 at the initiation codon of the VPS13A gene. There are no known alternative start codons in other transcripts that are expressed at detectable levels. This variant is expected to abolish protein translation (PVS1_Moderate). VPS13A:c.1A>T is absent from population databases (PM2). This variant has not been recorded in ClinVar. This variant is not on record in HGMD. This variant has not been described in the scientific literature. Variants damaging to normal protein function of VPS13A are highly specific for this disease and confirm a diagnosis of choreoacanthocytosis (PP4). Parental segregation testing has shown that these variants are in trans (PM3_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Uncertain	0.56	.;.;D;.;.;.;D
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-2.0	N;N;N;N;.;.;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;.
Polyphen		0.98	D;B;D;D;D;D;D
Vest4		0.83
MutPred		1.0		Loss of disorder (P = 0.1049);Loss of disorder (P = 0.1049);Loss of disorder (P = 0.1049);Loss of disorder (P = 0.1049);Loss of disorder (P = 0.1049);Loss of disorder (P = 0.1049);Loss of disorder (P = 0.1049);
MVP		0.77
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.92
gMVP		0.79

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: chr9-79792621;