rs17423984

Positions:

• chr9-77321499-A-G

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.5583A>G​(p.Thr1861=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0811 in 1,613,086 control chromosomes in the GnomAD database, including 6,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (369 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5694 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0190

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=-0.55).
• BP6: Variant 9-77321499-A-G is Benign according to our data. Variant chr9-77321499-A-G is described in ClinVar as [Benign]. Clinvar id is 367389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77321499-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.019 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.5583A>G	p.Thr1861=	synonymous_variant	44/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.5466A>G	p.Thr1822=	synonymous_variant	43/71		NP_001018047.1
VPS13A	NM_015186.4	c.5583A>G	p.Thr1861=	synonymous_variant	44/69		NP_056001.1
VPS13A	NM_001018038.3	c.5583A>G	p.Thr1861=	synonymous_variant	44/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.5583A>G	p.Thr1861=	synonymous_variant	44/72	1	NM_033305.3	ENSP00000353422	P4

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 8748 AN: 152040 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0570

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.0575

GnomAD3 exomes AF: 0.0715 AC: 17906 AN: 250270 Hom.: 830 AF XY: 0.0776 AC XY: 10501 AN XY: 135392

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.0303

Gnomad ASJ exome AF: 0.0683

Gnomad EAS exome AF: 0.000599

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.0623

Gnomad NFE exome AF: 0.0907

Gnomad OTH exome AF: 0.0748

GnomAD4 exome AF: 0.0836 AC: 122148 AN: 1460928 Hom.: 5694 Cov.: 32 AF XY: 0.0854 AC XY: 62050 AN XY: 726800

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.0323

Gnomad4 ASJ exome AF: 0.0695

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0648

Gnomad4 NFE exome AF: 0.0890

Gnomad4 OTH exome AF: 0.0742

GnomAD4 genome AF: 0.0575 AC: 8744 AN: 152158 Hom.: 369 Cov.: 32 AF XY: 0.0566 AC XY: 4208 AN XY: 74388

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0580

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.0570

Gnomad4 NFE AF: 0.0853

Gnomad4 OTH AF: 0.0564

Alfa AF: 0.0788 Hom.: 660

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.0844

EpiControl AF: 0.0867

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -

Chorea-acanthocytosis Benign:3

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.6
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs17423984; hg19: chr9-79936415; COSMIC: COSV62430010; COSMIC: COSV62430010;