NM_033305.3:c.3356G>A

Variant names:

• chr9-77293357-G-A
• rs144358567
• NM_033305.3:c.3356G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033305.3(VPS13A):​c.3356G>A​(p.Gly1119Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,612,310 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1119G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (24 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.46
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006241679).
• BP6: Variant 9-77293357-G-A is Benign according to our data. Variant chr9-77293357-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00214 (325/152190) while in subpopulation NFE AF = 0.00231 (157/68008). AF 95% confidence interval is 0.00201. There are 2 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	NM_033305.3	MANE Select	c.3356G>A	p.Gly1119Glu	missense	Exon 32 of 72	NP_150648.2
	VPS13A	NM_001018037.2		c.3239G>A	p.Gly1080Glu	missense	Exon 31 of 71	NP_001018047.1
	VPS13A	NM_015186.4		c.3356G>A	p.Gly1119Glu	missense	Exon 32 of 69	NP_056001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.3356G>A	p.Gly1119Glu	missense	Exon 32 of 72	ENSP00000353422.3
	VPS13A	ENST00000376636.7	TSL:1	c.3239G>A	p.Gly1080Glu	missense	Exon 31 of 71	ENSP00000365823.3
	VPS13A	ENST00000643348.1		c.3356G>A	p.Gly1119Glu	missense	Exon 32 of 69	ENSP00000493592.1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152072 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00310 AC: 776 AN: 250496 AF XY: 0.00303

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00255 AC: 3723 AN: 1460120 Hom.: 24 Cov.: 30 AF XY: 0.00260 AC XY: 1888 AN XY: 726380

African (AFR) AF: 0.000718 AC: 24 AN: 33410

American (AMR) AF: 0.00245 AC: 109 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 616 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86048

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53374

Middle Eastern (MID) AF: 0.00963 AC: 55 AN: 5714

European-Non Finnish (NFE) AF: 0.00230 AC: 2555 AN: 1111142

Other (OTH) AF: 0.00400 AC: 241 AN: 60308

GnomAD4 genome AF: 0.00214 AC: 325 AN: 152190 Hom.: 2 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74404

African (AFR) AF: 0.000626 AC: 26 AN: 41528

American (AMR) AF: 0.00196 AC: 30 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10576

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68008

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00233 Hom.: 9

Bravo AF: 0.00242

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00301 AC: 366

Asia WGS AF: 0.00145 AC: 5 AN: 3474

EpiCase AF: 0.00236

EpiControl AF: 0.00481

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Chorea-acanthocytosis (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.13
Sift	Benign	0.069	T
Sift4G	Benign	0.11	T
Polyphen		0.66	P
Vest4		0.32
MVP		0.67
MPC		0.20
ClinPred		0.051	T
GERP RS		3.6
Varity_R		0.27
gMVP		0.52
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: rs144358567; hg19: chr9-79908273; COSMIC: COSV62435546; COSMIC: COSV62435546;