rs17340192

Positions:

• chr9-77369316-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033305.3(VPS13A):​c.8571T>C​(p.Tyr2857Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 1,610,632 control chromosomes in the GnomAD database, including 6,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (378 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5633 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.30

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=-0.53).
• BP6: Variant 9-77369316-T-C is Benign according to our data. Variant chr9-77369316-T-C is described in ClinVar as [Benign]. Clinvar id is 367423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77369316-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.8571T>C	p.Tyr2857Tyr	synonymous_variant	63/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.8454T>C	p.Tyr2818Tyr	synonymous_variant	62/71		NP_001018047.1
VPS13A	NM_015186.4	c.8571T>C	p.Tyr2857Tyr	synonymous_variant	63/69		NP_056001.1
VPS13A	NM_001018038.3	c.8571T>C	p.Tyr2857Tyr	synonymous_variant	63/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.8571T>C	p.Tyr2857Tyr	synonymous_variant	63/72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.8454T>C	p.Tyr2818Tyr	synonymous_variant	62/71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.8571T>C	p.Tyr2857Tyr	synonymous_variant	63/69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.8571T>C	p.Tyr2857Tyr	synonymous_variant	63/69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9127 AN: 152178 Hom.: 377 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0567

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0721 AC: 18126 AN: 251378 Hom.: 836 AF XY: 0.0780 AC XY: 10591 AN XY: 135862

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.0304

Gnomad ASJ exome AF: 0.0685

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.0752

GnomAD4 exome AF: 0.0832 AC: 121299 AN: 1458336 Hom.: 5633 Cov.: 30 AF XY: 0.0849 AC XY: 61639 AN XY: 725708

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.0324

Gnomad4 ASJ exome AF: 0.0693

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.0647

Gnomad4 NFE exome AF: 0.0883

Gnomad4 OTH exome AF: 0.0740

GnomAD4 genome AF: 0.0599 AC: 9124 AN: 152296 Hom.: 378 Cov.: 33 AF XY: 0.0589 AC XY: 4387 AN XY: 74466

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.0471

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0567

Gnomad4 NFE AF: 0.0855

Gnomad4 OTH AF: 0.0568

Alfa AF: 0.0759 Hom.: 309

Bravo AF: 0.0566

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.0845

EpiControl AF: 0.0869

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	GeneDx	Sep 04, 2018	- -
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	-	- -

Chorea-acanthocytosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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, 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	-0.53
CADD	Benign	4.4
DANN	Benign	0.59

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: rs17340192; hg19: chr9-79984232; COSMIC: COSV62429716;