rs119477052

chr9-77205394-T-Achr9-77205394-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 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).

• 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

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 Likely_pathogenic. Variant got 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. Variant chr9-77205394-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.269T>A	p.Ile90Lys	missense_variant	4/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.269T>A	p.Ile90Lys	missense_variant	4/71
VPS13A	NM_015186.4	c.269T>A	p.Ile90Lys	missense_variant	4/69
VPS13A	NM_001018038.3	c.269T>A	p.Ile90Lys	missense_variant	4/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.269T>A	p.Ile90Lys	missense_variant	4/72	1	NM_033305.3	P4
VPS13A	ENST00000376636.7	c.269T>A	p.Ile90Lys	missense_variant	4/71	1
VPS13A	ENST00000643348.1	c.269T>A	p.Ile90Lys	missense_variant	4/69
VPS13A	ENST00000645632.1	c.269T>A	p.Ile90Lys	missense_variant	4/69			A1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

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
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	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
MutationTaster	Benign	1.0	A;A;A;A
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

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: rs119477052; hg19: chr9-79820310;