rs749375820

Variant names:

• chr9-77252352-A-G
• rs749375820
• NM_033305.3:c.2288A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033305.3(VPS13A):​c.2288A>G​(p.Lys763Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K763E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense, splice_region
• Scores: Splicing: ADA: 0.001931
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13161203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 71		NP_001018047.1
VPS13A	NM_015186.4	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 69		NP_056001.1
VPS13A	NM_001018038.3	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.2288A>G	p.Lys763Arg	missense_variant, splice_region_variant	Exon 22 of 69			ENSP00000496361.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454180 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724040

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105072

Other (OTH) AF: 0.00 AC: 0 AN: 60170

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 20, 2018

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	0.077
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;.;T;.;.;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	.;T;.;.;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L
PhyloP100		3.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.83	N;N;N;N;.;.;.
REVEL	Benign	0.049
Sift	Benign	0.49	T;T;T;T;.;.;.
Sift4G	Benign	0.61	T;T;T;T;.;.;.
Polyphen		0.031	B;B;B;B;B;B;B
Vest4		0.20
MutPred		0.50		Loss of methylation at K763 (P = 0.0286);Loss of methylation at K763 (P = 0.0286);Loss of methylation at K763 (P = 0.0286);Loss of methylation at K763 (P = 0.0286);Loss of methylation at K763 (P = 0.0286);Loss of methylation at K763 (P = 0.0286);Loss of methylation at K763 (P = 0.0286);
MVP		0.66
MPC		0.11
ClinPred		0.29	T
GERP RS		3.1
Varity_R		0.048
gMVP		0.58
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.090
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: rs749375820; hg19: chr9-79867268;