rs119477052

Variant names:

• chr9-77205394-T-A
• rs119477052
• NM_033305.3:c.269T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-77205394-T-A
• chr9-77205394-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_033305.3(VPS13A):​c.269T>A​(p.Ile90Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I90T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.37
• Publications: 7 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-77205394-T-A is Pathogenic according to our data. Variant chr9-77205394-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 4682.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 71		NP_001018047.1
VPS13A	NM_015186.4	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 69		NP_056001.1
VPS13A	NM_001018038.3	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.269T>A	p.Ile90Lys	missense_variant	Exon 4 of 69			ENSP00000496361.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chorea-acanthocytosis Pathogenic:1

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.87	.;.;D;.;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;D;.;.;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.6	M;M;M;M;M;M;M
PhyloP100		7.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;.;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.96
MutPred		0.91		Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);
MVP		0.95
MPC		0.78
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.91
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs119477052; hg19: chr9-79820310;