rs41307461

Variant names:

• chr9-77219974-A-G
• rs41307461
• NM_033305.3:c.775A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033305.3(VPS13A):​c.775A>G​(p.Asn259Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,613,546 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (24 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 2.06
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078703165).
• BP6: Variant 9-77219974-A-G is Benign according to our data. Variant chr9-77219974-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367346.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00249 (379/152168) while in subpopulation NFE AF = 0.00447 (304/67962). AF 95% confidence interval is 0.00406. There are 1 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 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.775A>G	p.Asn259Asp	missense	Exon 11 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.775A>G	p.Asn259Asp	missense	Exon 11 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.775A>G	p.Asn259Asp	missense	Exon 11 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.775A>G	p.Asn259Asp	missense	Exon 11 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.775A>G	p.Asn259Asp	missense	Exon 11 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000643348.1		c.775A>G	p.Asn259Asp	missense	Exon 11 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152050 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00239 AC: 601 AN: 251160 AF XY: 0.00220

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00379 AC: 5535 AN: 1461378 Hom.: 24 Cov.: 31 AF XY: 0.00358 AC XY: 2600 AN XY: 726990

African (AFR) AF: 0.000717 AC: 24 AN: 33456

American (AMR) AF: 0.000693 AC: 31 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.00140 AC: 75 AN: 53410

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00459 AC: 5099 AN: 1111684

Other (OTH) AF: 0.00335 AC: 202 AN: 60360

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152168 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74394

African (AFR) AF: 0.000987 AC: 41 AN: 41550

American (AMR) AF: 0.000393 AC: 6 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 67962

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00318 Hom.: 0

Bravo AF: 0.00220

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00265 AC: 322

EpiCase AF: 0.00387

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	2	2	Chorea-acanthocytosis (4)
-	-	1	VPS13A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.063
Sift	Benign	0.12	T
Sift4G	Benign	0.43	T
Polyphen		0.0040	B
Vest4		0.21
MVP		0.45
MPC		0.15
ClinPred		0.0065	T
GERP RS		-0.0091
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.38
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs41307461; hg19: chr9-79834890;