rs1554681451

Variant names:

• chr9-77405899-A-G
• rs1554681451
• NM_033305.3:c.9311A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033305.3(VPS13A):​c.9311A>G​(p.Gln3104Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q3104Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.56
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.9311A>G	p.Gln3104Arg	missense_variant	Exon 70 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.9194A>G	p.Gln3065Arg	missense_variant	Exon 69 of 71		NP_001018047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.9311A>G	p.Gln3104Arg	missense_variant	Exon 70 of 72	1	NM_033305.3	ENSP00000353422.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.2	.;M;M
PhyloP100		8.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.25
Sift	Benign	0.18	T;T;.
Sift4G	Benign	0.082	T;T;.
Polyphen		0.83	P;D;D
Vest4		0.48
MutPred		0.54		.;Gain of MoRF binding (P = 0.029);Gain of MoRF binding (P = 0.029);
MVP		0.89
MPC		0.62
ClinPred		0.94	D
GERP RS		5.9
PromoterAI		0.056	Neutral
Varity_R		0.20
gMVP		0.55
Mutation Taster		=58/42	polymorphism

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: rs1554681451; hg19: chr9-80020815;