9-77177524-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000376636.7(VPS13A):c.-181G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 604,510 control chromosomes in the GnomAD database, including 6,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1209 hom., cov: 33)
  • Exomes 𝑓: 0.14 (5058 hom.)
• Consequence: VPS13A ENST00000376636.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0420

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-77177524-G-A is Benign according to our data. Variant chr9-77177524-G-A is described in ClinVar as [Benign]. Clinvar id is 367338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A-AS1	NR_026668.2	n.291+103C>T		intron_variant, non_coding_transcript_variant
VPS13A	NM_033305.3			upstream_gene_variant		ENST00000360280.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A-AS1	ENST00000644612.1	n.554+103C>T		intron_variant, non_coding_transcript_variant
VPS13A	ENST00000360280.8			upstream_gene_variant		1	NM_033305.3	P4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16332 AN: 152128 Hom.: 1207 Cov.: 33

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.0992

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.137 AC: 62166 AN: 452266 Hom.: 5058 Cov.: 5 AF XY: 0.141 AC XY: 34207 AN XY: 242514

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.0807

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.000391

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.107 AC: 16328 AN: 152244 Hom.: 1209 Cov.: 33 AF XY: 0.105 AC XY: 7821 AN XY: 74440

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.0989

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.130

Alfa AF: 0.129 Hom.: 193

Bravo AF: 0.103

Asia WGS AF: 0.0690 AC: 241 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chorea-acanthocytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	9.0
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117488726; hg19: chr9-79792440;