rs1057520049

Variant names:

• chr9-77360639-G-T
• rs1057520049
• NM_033305.3:c.8209G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_033305.3(VPS13A):​c.8209G>T​(p.Glu2737*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13A NM_033305.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9761
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.86
• Publications: 1 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: Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 9-77360639-G-T is Pathogenic according to our data. Variant chr9-77360639-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376770.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.8209G>T	p.Glu2737*	stop_gained, splice_region_variant	Exon 59 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.8092G>T	p.Glu2698*	stop_gained, splice_region_variant	Exon 58 of 71		NP_001018047.1
VPS13A	NM_015186.4	c.8209G>T	p.Glu2737*	stop_gained, splice_region_variant	Exon 59 of 69		NP_056001.1
VPS13A	NM_001018038.3	c.8209G>T	p.Glu2737*	stop_gained, splice_region_variant	Exon 59 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.8209G>T	p.Glu2737*	stop_gained, splice_region_variant	Exon 59 of 72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.8092G>T	p.Glu2698*	stop_gained, splice_region_variant	Exon 58 of 71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.8209G>T	p.Glu2737*	stop_gained, splice_region_variant	Exon 59 of 69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.8209G>T	p.Glu2737*	stop_gained, splice_region_variant	Exon 59 of 69			ENSP00000496361.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		2.9
Vest4		0.84
GERP RS		5.6
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.010		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: rs1057520049; hg19: chr9-79975555;