rs139753431

Positions:

• chr9-77344179-T-C
• chr9-77344179-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_033305.3(VPS13A):​c.7053T>C​(p.Ala2351Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,609,510 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (14 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.639

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-77344179-T-C is Benign according to our data. Variant chr9-77344179-T-C is described in ClinVar as [Benign]. Clinvar id is 448870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77344179-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.639 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00575 (876/152248) while in subpopulation AFR AF= 0.0203 (845/41558). AF 95% confidence interval is 0.0192. There are 12 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.7053T>C	p.Ala2351Ala	synonymous_variant	51/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.6936T>C	p.Ala2312Ala	synonymous_variant	50/71		NP_001018047.1
VPS13A	NM_015186.4	c.7053T>C	p.Ala2351Ala	synonymous_variant	51/69		NP_056001.1
VPS13A	NM_001018038.3	c.7053T>C	p.Ala2351Ala	synonymous_variant	51/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.7053T>C	p.Ala2351Ala	synonymous_variant	51/72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.6936T>C	p.Ala2312Ala	synonymous_variant	50/71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.7053T>C	p.Ala2351Ala	synonymous_variant	51/69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.7053T>C	p.Ala2351Ala	synonymous_variant	51/69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 873 AN: 152130 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

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: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00156 AC: 393 AN: 251326 Hom.: 6 AF XY: 0.00110 AC XY: 149 AN XY: 135870

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000620 AC: 904 AN: 1457262 Hom.: 14 Cov.: 30 AF XY: 0.000567 AC XY: 411 AN XY: 725260

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152248 Hom.: 12 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74450

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.00692

Asia WGS AF: 0.000578 AC: 2 AN: 3472

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 18, 2018	- -

Chorea-acanthocytosis Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.9
DANN	Benign	0.58

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: rs139753431; hg19: chr9-79959095;