rs17423984

Variant names:

• chr9-77321499-A-G
• rs17423984
• NM_033305.3:c.5583A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033305.3(VPS13A):​c.5583A>G​(p.Thr1861Thr) 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
• Publications: 12 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 Gene-Disease associations (from GenCC):

• chorea-acanthocytosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.009).
• BP6: Variant 9-77321499-A-G is Benign according to our data. Variant chr9-77321499-A-G is described in ClinVar as Benign. ClinVar VariationId is 367389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033305.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	NM_033305.3	MANE Select	c.5583A>G	p.Thr1861Thr	synonymous	Exon 44 of 72	NP_150648.2
	VPS13A	NM_001018037.2		c.5466A>G	p.Thr1822Thr	synonymous	Exon 43 of 71	NP_001018047.1
	VPS13A	NM_015186.4		c.5583A>G	p.Thr1861Thr	synonymous	Exon 44 of 69	NP_056001.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.5583A>G	p.Thr1861Thr	synonymous	Exon 44 of 72	ENSP00000353422.3
	VPS13A	ENST00000376636.7	TSL:1	c.5466A>G	p.Thr1822Thr	synonymous	Exon 43 of 71	ENSP00000365823.3
	VPS13A	ENST00000419472.1	TSL:1	c.339A>G	p.Thr113Thr	synonymous	Exon 4 of 7	ENSP00000414410.1

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

GnomAD2 exomes AF: 0.0715 AC: 17906 AN: 250270 AF XY: 0.0776

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 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

African (AFR) AF: 0.0123 AC: 413 AN: 33450

American (AMR) AF: 0.0323 AC: 1441 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 1815 AN: 26108

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39644

South Asian (SAS) AF: 0.127 AC: 10971 AN: 86212

European-Finnish (FIN) AF: 0.0648 AC: 3457 AN: 53380

Middle Eastern (MID) AF: 0.108 AC: 621 AN: 5744

European-Non Finnish (NFE) AF: 0.0890 AC: 98944 AN: 1111396

Other (OTH) AF: 0.0742 AC: 4477 AN: 60350

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

African (AFR) AF: 0.0156 AC: 647 AN: 41570

American (AMR) AF: 0.0466 AC: 713 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3464

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.122 AC: 587 AN: 4818

European-Finnish (FIN) AF: 0.0570 AC: 605 AN: 10622

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0853 AC: 5792 AN: 67896

Other (OTH) AF: 0.0564 AC: 119 AN: 2110

Alfa AF: 0.0762 Hom.: 785

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.0844

EpiControl AF: 0.0867

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Chorea-acanthocytosis (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.6
DANN	Benign	0.67
PhyloP100		-0.019
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17423984; hg19: chr9-79936415; COSMIC: COSV62430010; COSMIC: COSV62430010;