rs146280301

Variant names:

• chr9-77321541-A-G
• rs146280301
• NM_033305.3:c.5625A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_033305.3(VPS13A):​c.5625A>G​(p.Leu1875Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,544 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1875L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0058 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (14 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 9-77321541-A-G is Benign according to our data. Variant chr9-77321541-A-G is described in ClinVar as Benign. ClinVar VariationId is 448867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00577 (878/152228) while in subpopulation AFR AF = 0.0204 (846/41562). AF 95% confidence interval is 0.0192. There are 12 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	NM_033305.3	MANE Select	c.5625A>G	p.Leu1875Leu	synonymous	Exon 44 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.5508A>G	p.Leu1836Leu	synonymous	Exon 43 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.5625A>G	p.Leu1875Leu	synonymous	Exon 44 of 69	NP_056001.1	Q96RL7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.5625A>G	p.Leu1875Leu	synonymous	Exon 44 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.5508A>G	p.Leu1836Leu	synonymous	Exon 43 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000419472.1	TSL:1	c.381A>G	p.Leu127Leu	synonymous	Exon 4 of 7	ENSP00000414410.1	H0Y7P8

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152110 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00158 AC: 395 AN: 250772 AF XY: 0.00111

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000631 AC: 922 AN: 1461316 Hom.: 14 Cov.: 32 AF XY: 0.000579 AC XY: 421 AN XY: 726934

African (AFR) AF: 0.0229 AC: 767 AN: 33450

American (AMR) AF: 0.000918 AC: 41 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111690

Other (OTH) AF: 0.00142 AC: 86 AN: 60368

GnomAD4 genome AF: 0.00577 AC: 878 AN: 152228 Hom.: 12 Cov.: 32 AF XY: 0.00550 AC XY: 409 AN XY: 74426

African (AFR) AF: 0.0204 AC: 846 AN: 41562

American (AMR) AF: 0.00137 AC: 21 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67952

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00259 Hom.: 3

Bravo AF: 0.00693

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Chorea-acanthocytosis (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.8
DANN	Benign	0.47
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146280301; hg19: chr9-79936457; COSMIC: COSV100652683; COSMIC: COSV100652683;