rs776549674

Positions:

• chr9-77228167-G-A
• chr9-77228167-G-C
• chr9-77228167-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033305.3(VPS13A):​c.1498G>A​(p.Val500Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.932

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077531874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.1498G>A	p.Val500Ile	missense_variant	17/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.1498G>A	p.Val500Ile	missense_variant	17/71		NP_001018047.1
VPS13A	NM_015186.4	c.1498G>A	p.Val500Ile	missense_variant	17/69		NP_056001.1
VPS13A	NM_001018038.3	c.1498G>A	p.Val500Ile	missense_variant	17/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.1498G>A	p.Val500Ile	missense_variant	17/72	1	NM_033305.3	ENSP00000353422	P4
VPS13A	ENST00000376636.7	c.1498G>A	p.Val500Ile	missense_variant	17/71	1		ENSP00000365823
VPS13A	ENST00000643348.1	c.1498G>A	p.Val500Ile	missense_variant	17/69			ENSP00000493592
VPS13A	ENST00000645632.1	c.1498G>A	p.Val500Ile	missense_variant	17/69			ENSP00000496361	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452158 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.15	.;.;T;.;.;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.75	.;T;.;.;T;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.078	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.27	N;N;N;N;.;.;.
REVEL	Benign	0.036
Sift	Benign	0.50	T;T;T;T;.;.;.
Sift4G	Benign	0.38	T;T;T;T;.;.;.
Polyphen		0.0020	B;B;B;B;B;B;B
Vest4		0.086
MutPred		0.35		Loss of catalytic residue at V500 (P = 0.0054);Loss of catalytic residue at V500 (P = 0.0054);Loss of catalytic residue at V500 (P = 0.0054);Loss of catalytic residue at V500 (P = 0.0054);Loss of catalytic residue at V500 (P = 0.0054);Loss of catalytic residue at V500 (P = 0.0054);Loss of catalytic residue at V500 (P = 0.0054);
MVP		0.32
MPC		0.10
ClinPred		0.12	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.21

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: rs776549674; hg19: chr9-79843083;