rs7025532

Variant names:

• chr9-77339629-T-C
• rs7025532
• NM_033305.3:c.6492T>C

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.6492T>C​(p.Asp2164Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,613,058 control chromosomes in the GnomAD database, including 30,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2827 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27448 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.102
• Publications: 19 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 (BayesDel_noAF=-0.57).
• BP6: Variant 9-77339629-T-C is Benign according to our data. Variant chr9-77339629-T-C is described in ClinVar as Benign. ClinVar VariationId is 367402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 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.6492T>C	p.Asp2164Asp	synonymous	Exon 48 of 72	NP_150648.2
	VPS13A	NM_001018037.2		c.6375T>C	p.Asp2125Asp	synonymous	Exon 47 of 71	NP_001018047.1
	VPS13A	NM_015186.4		c.6492T>C	p.Asp2164Asp	synonymous	Exon 48 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.6492T>C	p.Asp2164Asp	synonymous	Exon 48 of 72	ENSP00000353422.3
	VPS13A	ENST00000376636.7	TSL:1	c.6375T>C	p.Asp2125Asp	synonymous	Exon 47 of 71	ENSP00000365823.3
	VPS13A	ENST00000643348.1		c.6492T>C	p.Asp2164Asp	synonymous	Exon 48 of 69	ENSP00000493592.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28388 AN: 151836 Hom.: 2823 Cov.: 31

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.168 AC: 42021 AN: 250428 AF XY: 0.173

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0800

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.189 AC: 275558 AN: 1461104 Hom.: 27448 Cov.: 36 AF XY: 0.189 AC XY: 137658 AN XY: 726794

African (AFR) AF: 0.223 AC: 7448 AN: 33464

American (AMR) AF: 0.0855 AC: 3817 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4594 AN: 26124

East Asian (EAS) AF: 0.0307 AC: 1218 AN: 39670

South Asian (SAS) AF: 0.208 AC: 17932 AN: 86210

European-Finnish (FIN) AF: 0.183 AC: 9773 AN: 53376

Middle Eastern (MID) AF: 0.221 AC: 1272 AN: 5758

European-Non Finnish (NFE) AF: 0.197 AC: 218756 AN: 1111492

Other (OTH) AF: 0.178 AC: 10748 AN: 60356

GnomAD4 genome AF: 0.187 AC: 28420 AN: 151954 Hom.: 2827 Cov.: 31 AF XY: 0.184 AC XY: 13666 AN XY: 74262

African (AFR) AF: 0.219 AC: 9096 AN: 41450

American (AMR) AF: 0.133 AC: 2030 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3468

East Asian (EAS) AF: 0.0340 AC: 176 AN: 5178

South Asian (SAS) AF: 0.198 AC: 949 AN: 4802

European-Finnish (FIN) AF: 0.177 AC: 1866 AN: 10542

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13196 AN: 67942

Other (OTH) AF: 0.162 AC: 342 AN: 2108

Alfa AF: 0.190 Hom.: 8598

Bravo AF: 0.184

Asia WGS AF: 0.108 AC: 379 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Chorea-acanthocytosis (4)
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.5
DANN	Benign	0.47
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7025532; hg19: chr9-79954545; COSMIC: COSV62430039; COSMIC: COSV62430039;