rs114232513

Positions:

• chr9-77339547-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033305.3(VPS13A):​c.6410A>G​(p.Glu2137Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000989 in 1,568,116 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.89

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00822413).
• BP6: Variant 9-77339547-A-G is Benign according to our data. Variant chr9-77339547-A-G is described in ClinVar as [Benign]. Clinvar id is 367401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77339547-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00532 (805/151224) while in subpopulation AFR AF= 0.0184 (760/41240). AF 95% confidence interval is 0.0173. There are 8 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.6410A>G	p.Glu2137Gly	missense_variant	48/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.6293A>G	p.Glu2098Gly	missense_variant	47/71		NP_001018047.1
VPS13A	NM_015186.4	c.6410A>G	p.Glu2137Gly	missense_variant	48/69		NP_056001.1
VPS13A	NM_001018038.3	c.6410A>G	p.Glu2137Gly	missense_variant	48/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.6410A>G	p.Glu2137Gly	missense_variant	48/72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.6293A>G	p.Glu2098Gly	missense_variant	47/71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.6410A>G	p.Glu2137Gly	missense_variant	48/69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.6410A>G	p.Glu2137Gly	missense_variant	48/69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 806 AN: 151112 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

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: 0.0000884

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00134 AC: 251 AN: 186742 Hom.: 2 AF XY: 0.000998 AC XY: 99 AN XY: 99154

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.000742

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000400

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000391

Gnomad OTH exome AF: 0.000792

GnomAD4 exome AF: 0.000527 AC: 746 AN: 1416892 Hom.: 4 Cov.: 35 AF XY: 0.000422 AC XY: 296 AN XY: 700960

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.000956

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00532 AC: 805 AN: 151224 Hom.: 8 Cov.: 31 AF XY: 0.00534 AC XY: 394 AN XY: 73780

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000885

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.000930 Hom.: 1

Bravo AF: 0.00623

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00135 AC: 162

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Chorea-acanthocytosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;D;.;.;.;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	.;D;.;.;D;D;D
MetaRNN	Benign	0.0082	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M;.;M;M;M;M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.3	D;D;D;D;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;D;D;D;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;.;.;.
Polyphen		0.36	B;B;B;B;B;B;B
Vest4		0.34
MVP		0.71
MPC		0.39
ClinPred		0.071	T
GERP RS		5.9
Varity_R		0.23
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs114232513; hg19: chr9-79954463;