rs41289967

Variant names:

• chr9-77316185-G-A
• rs41289967
• NM_033305.3:c.4642G>A
• VPS13A p.Glu1548Lys

Your query was ambiguous. Multiple possible variants found:

• chr9-77316185-G-A
• chr9-77316185-G-C

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.4642G>A​(p.Glu1548Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,608,202 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. E1548E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0870
• Publications: 7 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: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038916469).
• BP6: Variant 9-77316185-G-A is Benign according to our data. Variant chr9-77316185-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 448863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00211 (320/151702) while in subpopulation AMR AF = 0.00355 (54/15220). AF 95% confidence interval is 0.00281. There are 2 homozygotes in GnomAd4. There are 148 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.4642G>A	p.Glu1548Lys	missense	Exon 39 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.4525G>A	p.Glu1509Lys	missense	Exon 38 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.4642G>A	p.Glu1548Lys	missense	Exon 39 of 69	NP_056001.1	Q96RL7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.4642G>A	p.Glu1548Lys	missense	Exon 39 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.4525G>A	p.Glu1509Lys	missense	Exon 38 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000643348.1		c.4642G>A	p.Glu1548Lys	missense	Exon 39 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 320 AN: 151584 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00355

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00206 AC: 514 AN: 249830 AF XY: 0.00216

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00253 AC: 3687 AN: 1456500 Hom.: 12 Cov.: 30 AF XY: 0.00247 AC XY: 1791 AN XY: 724712

African (AFR) AF: 0.000510 AC: 17 AN: 33324

American (AMR) AF: 0.00173 AC: 77 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00480 AC: 125 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000209 AC: 18 AN: 85968

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53250

Middle Eastern (MID) AF: 0.00610 AC: 35 AN: 5734

European-Non Finnish (NFE) AF: 0.00289 AC: 3204 AN: 1107802

Other (OTH) AF: 0.00322 AC: 194 AN: 60172

GnomAD4 genome AF: 0.00211 AC: 320 AN: 151702 Hom.: 2 Cov.: 32 AF XY: 0.00200 AC XY: 148 AN XY: 74120

African (AFR) AF: 0.000435 AC: 18 AN: 41420

American (AMR) AF: 0.00355 AC: 54 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10500

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

European-Non Finnish (NFE) AF: 0.00316 AC: 214 AN: 67826

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00272 Hom.: 4

Bravo AF: 0.00214

EpiCase AF: 0.00306

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Chorea-acanthocytosis (3)
-	-	2	not specified (2)
-	-	1	VPS13A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.8
DANN	Benign	0.78
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.096	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.087
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.045
Sift	Benign	0.44	T
Sift4G	Benign	0.56	T
Varity_R		0.084
gMVP		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41289967;

hg19: chr9-79931101;