chr9-77228167-G-C

Variant names:

• chr9-77228167-G-C
• rs776549674
• NM_033305.3:c.1498G>C

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.1498G>C​(p.Val500Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,604,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V500F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.932
• Publications: 1 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=0.10757336).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033305.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	NM_033305.3	MANE Select	c.1498G>C	p.Val500Leu	missense	Exon 17 of 72	NP_150648.2
	VPS13A	NM_001018037.2		c.1498G>C	p.Val500Leu	missense	Exon 17 of 71	NP_001018047.1
	VPS13A	NM_015186.4		c.1498G>C	p.Val500Leu	missense	Exon 17 of 69	NP_056001.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.1498G>C	p.Val500Leu	missense	Exon 17 of 72	ENSP00000353422.3
	VPS13A	ENST00000376636.7	TSL:1	c.1498G>C	p.Val500Leu	missense	Exon 17 of 71	ENSP00000365823.3
	VPS13A	ENST00000643348.1		c.1498G>C	p.Val500Leu	missense	Exon 17 of 69	ENSP00000493592.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 242574 AF XY: 0.0000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452158 Hom.: 0 Cov.: 30 AF XY: 0.00000416 AC XY: 3 AN XY: 721904

African (AFR) AF: 0.00 AC: 0 AN: 33254

American (AMR) AF: 0.0000226 AC: 1 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 84928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4802

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107148

Other (OTH) AF: 0.00 AC: 0 AN: 59888

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151908 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74188

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.0000657 AC: 1 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.93
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.014
Sift	Benign	0.22	T
Sift4G	Benign	0.12	T
Polyphen		0.038	B
Vest4		0.36
MutPred		0.38		Loss of catalytic residue at V500 (P = 0.0132)
MVP		0.40
MPC		0.13
ClinPred		0.13	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.36
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776549674; hg19: chr9-79843083;