9-77177524-G-A

Variant names:

• chr9-77177524-G-A
• rs117488726
• ENST00000376636.7:c.-181G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.0420
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.-181G>A		upstream_gene_variant		ENST00000360280.8	NP_150648.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.-181G>A		upstream_gene_variant		1	NM_033305.3	ENSP00000353422.3

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

African (AFR) AF: 0.0276 AC: 331 AN: 12014

American (AMR) AF: 0.0807 AC: 1972 AN: 24448

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 2554 AN: 13734

East Asian (EAS) AF: 0.000391 AC: 11 AN: 28146

South Asian (SAS) AF: 0.181 AC: 9175 AN: 50652

European-Finnish (FIN) AF: 0.101 AC: 2772 AN: 27534

Middle Eastern (MID) AF: 0.177 AC: 341 AN: 1926

European-Non Finnish (NFE) AF: 0.155 AC: 41627 AN: 268762

Other (OTH) AF: 0.135 AC: 3383 AN: 25050

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

African (AFR) AF: 0.0294 AC: 1224 AN: 41568

American (AMR) AF: 0.0989 AC: 1514 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3470

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5166

South Asian (SAS) AF: 0.168 AC: 812 AN: 4826

European-Finnish (FIN) AF: 0.0896 AC: 950 AN: 10604

Middle Eastern (MID) AF: 0.200 AC: 58 AN: 290

European-Non Finnish (NFE) AF: 0.157 AC: 10668 AN: 67990

Other (OTH) AF: 0.130 AC: 274 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Chorea-acanthocytosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.0
DANN	Benign	0.89
PhyloP100		0.042
PromoterAI		0.055	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117488726; hg19: chr9-79792440;