chr9-77177522-G-C

Variant names:

• chr9-77177522-G-C
• rs12349389
• ENST00000376636:c.-183G>C

Variant summary

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

The ENST00000376636(VPS13A):​c.-183G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 599,262 control chromosomes in the GnomAD database, including 3,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (828 hom., cov: 33)
  • Exomes 𝑓: 0.097 (2317 hom.)
• Consequence: VPS13A ENST00000376636 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.100

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=-0.66).
• BP6: Variant 9-77177522-G-C is Benign according to our data. Variant chr9-77177522-G-C is described in ClinVar as [Benign]. Clinvar id is 367337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.-183G>C		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.-183G>C		upstream_gene_variant		1	NM_033305.3	ENSP00000353422.3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15592 AN: 152060 Hom.: 828 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0745

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0360

Gnomad SAS AF: 0.0750

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0947

GnomAD4 exome AF: 0.0966 AC: 43192 AN: 447084 Hom.: 2317 Cov.: 5 AF XY: 0.0961 AC XY: 23026 AN XY: 239622

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0522

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.0802

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.0948

GnomAD4 genome AF: 0.103 AC: 15606 AN: 152178 Hom.: 828 Cov.: 33 AF XY: 0.102 AC XY: 7570 AN XY: 74420

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0745

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.0361

Gnomad4 SAS AF: 0.0751

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.0342 Hom.: 29

Bravo AF: 0.0992

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.66
CADD	Benign	8.1
DANN	Benign	0.76

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

LitVar

Other links and lift over

dbSNP: rs12349389; hg19: chr9-79792438;