NM_033305.3:c.904C>T

Variant names:

• chr9-77220298-C-T
• rs541051874
• NM_033305.3:c.904C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033305.3(VPS13A):​c.904C>T​(p.Leu302Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,611,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L302L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.12
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25796804).

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.904C>T	p.Leu302Phe	missense	Exon 12 of 72	NP_150648.2
	VPS13A	NM_001018037.2		c.904C>T	p.Leu302Phe	missense	Exon 12 of 71	NP_001018047.1
	VPS13A	NM_015186.4		c.904C>T	p.Leu302Phe	missense	Exon 12 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.904C>T	p.Leu302Phe	missense	Exon 12 of 72	ENSP00000353422.3
	VPS13A	ENST00000376636.7	TSL:1	c.904C>T	p.Leu302Phe	missense	Exon 12 of 71	ENSP00000365823.3
	VPS13A	ENST00000643348.1		c.904C>T	p.Leu302Phe	missense	Exon 12 of 69	ENSP00000493592.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151724 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249876 AF XY: 0.0000222

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460050 Hom.: 1 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726278

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.000221 AC: 19 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111056

Other (OTH) AF: 0.0000332 AC: 2 AN: 60276

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151824 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74164

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67920

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Chorea-acanthocytosis (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.29
Sift	Benign	0.038	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.47		Loss of catalytic residue at M299 (P = 0.0695)
MVP		0.61
MPC		0.57
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.65
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs541051874; hg19: chr9-79835214;