9-77177705-A-T

Variant names:

• chr9-77177705-A-T
• NM_033305.3:c.1A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_033305.3(VPS13A):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 108 codons. Genomic position: 77206016. Lost 0.034 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 72	ENST00000360280.8	NP_150648.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 72	1	NM_033305.3	ENSP00000353422.3

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

Feb 07, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;