rs145346590

Positions:

• chr9-77276211-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_033305.3(VPS13A):​c.2814A>G​(p.Pro938Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,605,906 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (3 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.183

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-77276211-A-G is Benign according to our data. Variant chr9-77276211-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586928.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr9-77276211-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.183 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000893 (136/152304) while in subpopulation AMR AF= 0.00464 (71/15302). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.2814A>G	p.Pro938Pro	synonymous_variant	26/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.2814A>G	p.Pro938Pro	synonymous_variant	26/71		NP_001018047.1
VPS13A	NM_015186.4	c.2814A>G	p.Pro938Pro	synonymous_variant	26/69		NP_056001.1
VPS13A	NM_001018038.3	c.2814A>G	p.Pro938Pro	synonymous_variant	26/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.2814A>G	p.Pro938Pro	synonymous_variant	26/72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.2814A>G	p.Pro938Pro	synonymous_variant	26/71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.2814A>G	p.Pro938Pro	synonymous_variant	26/69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.2814A>G	p.Pro938Pro	synonymous_variant	26/69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

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: 0.000794

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000576 AC: 143 AN: 248200 Hom.: 1 AF XY: 0.000507 AC XY: 68 AN XY: 134142

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.000559

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000658 AC: 956 AN: 1453602 Hom.: 3 Cov.: 31 AF XY: 0.000637 AC XY: 460 AN XY: 722402

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.000633

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74472

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000967

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Chorea-acanthocytosis Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.2
DANN	Benign	0.75

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: rs145346590; hg19: chr9-79891127;