rs149037185

Positions:

• chr9-77238164-T-C
• chr9-77238164-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033305.3(VPS13A):​c.1758T>C​(p.Ala586=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,638 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.244

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 9-77238164-T-C is Benign according to our data. Variant chr9-77238164-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 367357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77238164-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00196 (298/152328) while in subpopulation AMR AF= 0.00314 (48/15300). AF 95% confidence interval is 0.00272. There are 2 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.1758T>C	p.Ala586=	synonymous_variant	18/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.1758T>C	p.Ala586=	synonymous_variant	18/71
VPS13A	NM_015186.4	c.1758T>C	p.Ala586=	synonymous_variant	18/69
VPS13A	NM_001018038.3	c.1758T>C	p.Ala586=	synonymous_variant	18/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.1758T>C	p.Ala586=	synonymous_variant	18/72	1	NM_033305.3	P4
VPS13A	ENST00000376636.7	c.1758T>C	p.Ala586=	synonymous_variant	18/71	1
VPS13A	ENST00000643348.1	c.1758T>C	p.Ala586=	synonymous_variant	18/69
VPS13A	ENST00000645632.1	c.1758T>C	p.Ala586=	synonymous_variant	18/69			A1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00194 AC: 487 AN: 250934 Hom.: 1 AF XY: 0.00205 AC XY: 278 AN XY: 135738

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00241 AC: 3515 AN: 1461310 Hom.: 11 Cov.: 32 AF XY: 0.00235 AC XY: 1709 AN XY: 726978

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74494

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.00190

EpiCase AF: 0.00284

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	VPS13A: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Chorea-acanthocytosis Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 17, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.0
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149037185; hg19: chr9-79853080;