rs3737289

Positions:

• chr9-77371141-A-G
• chr9-77371141-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033305.3(VPS13A):​c.9069A>G​(p.Gly3023=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,613,544 control chromosomes in the GnomAD database, including 156,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12981 hom., cov: 32)
  • Exomes 𝑓: 0.44 (143795 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.349

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-77371141-A-G is Benign according to our data. Variant chr9-77371141-A-G is described in ClinVar as [Benign]. Clinvar id is 367428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77371141-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.349 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.9069A>G	p.Gly3023=	synonymous_variant	67/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.8952A>G	p.Gly2984=	synonymous_variant	66/71
VPS13A	NM_015186.4	c.9069A>G	p.Gly3023=	synonymous_variant	67/69
VPS13A	NM_001018038.3	c.9069A>G	p.Gly3023=	synonymous_variant	67/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.9069A>G	p.Gly3023=	synonymous_variant	67/72	1	NM_033305.3	P4
VPS13A	ENST00000376636.7	c.8952A>G	p.Gly2984=	synonymous_variant	66/71	1
VPS13A	ENST00000643348.1	c.9069A>G	p.Gly3023=	synonymous_variant	67/69
VPS13A	ENST00000645632.1	c.9069A>G	p.Gly3023=	synonymous_variant	67/69			A1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61972 AN: 151926 Hom.: 12970 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.398

GnomAD3 exomes AF: 0.454 AC: 113950 AN: 250736 Hom.: 26527 AF XY: 0.456 AC XY: 61851 AN XY: 135560

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.576

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.542

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.433

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.441 AC: 643904 AN: 1461500 Hom.: 143795 Cov.: 55 AF XY: 0.443 AC XY: 321733 AN XY: 727056

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.558

Gnomad4 ASJ exome AF: 0.413

Gnomad4 EAS exome AF: 0.339

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.449

Gnomad4 NFE exome AF: 0.437

Gnomad4 OTH exome AF: 0.425

GnomAD4 genome AF: 0.408 AC: 62012 AN: 152044 Hom.: 12981 Cov.: 32 AF XY: 0.411 AC XY: 30571 AN XY: 74308

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.490

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.525

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.400

Alfa AF: 0.420 Hom.: 25167

Bravo AF: 0.406

Asia WGS AF: 0.422 AC: 1467 AN: 3478

EpiCase AF: 0.434

EpiControl AF: 0.431

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chorea-acanthocytosis Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.2
DANN	Benign	0.69

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: rs3737289; hg19: chr9-79986057; COSMIC: COSV62426716;