rs117320408

Positions:

• chr9-77252265-G-A
• chr9-77252265-G-C
• chr9-77252265-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033305.3(VPS13A):​c.2201G>A​(p.Ser734Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,974 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S734S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.738

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054429173).
• BP6: Variant 9-77252265-G-A is Benign according to our data. Variant chr9-77252265-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 367364.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}. Variant chr9-77252265-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00149 (2184/1461678) while in subpopulation NFE AF= 0.00189 (2102/1111860). AF 95% confidence interval is 0.00182. There are 5 homozygotes in gnomad4_exome. There are 1053 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.2201G>A	p.Ser734Asn	missense_variant	22/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.2201G>A	p.Ser734Asn	missense_variant	22/71
VPS13A	NM_015186.4	c.2201G>A	p.Ser734Asn	missense_variant	22/69
VPS13A	NM_001018038.3	c.2201G>A	p.Ser734Asn	missense_variant	22/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.2201G>A	p.Ser734Asn	missense_variant	22/72	1	NM_033305.3	P4
VPS13A	ENST00000376636.7	c.2201G>A	p.Ser734Asn	missense_variant	22/71	1
VPS13A	ENST00000643348.1	c.2201G>A	p.Ser734Asn	missense_variant	22/69
VPS13A	ENST00000645632.1	c.2201G>A	p.Ser734Asn	missense_variant	22/69			A1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000632 AC: 159 AN: 251434 Hom.: 0 AF XY: 0.000692 AC XY: 94 AN XY: 135896

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00149 AC: 2184 AN: 1461678 Hom.: 5 Cov.: 31 AF XY: 0.00145 AC XY: 1053 AN XY: 727146

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74464

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.00147

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chorea-acanthocytosis Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 05, 2020	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	VPS13A: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 734 of the VPS13A protein (p.Ser734Asn). This variant is present in population databases (rs117320408, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. ClinVar contains an entry for this variant (Variation ID: 367364). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 03, 2024	Variant summary: VPS13A c.2201G>A (p.Ser734Asn) results in a conservative amino acid change located in the middle RBG modules region (IPR031642) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 1607002 control chromosomes in the gnomAD database (v4.1 dataset), including 5 homozygotes. The observed variant frequency is approximately 1.3-fold of the estimated maximal expected allele frequency for a pathogenic variant in VPS13A causing Choreoacanthocytosis phenotype (0.0011). To our knowledge, no occurrence of c.2201G>A in individuals affected with Choreoacanthocytosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 367364). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.28
DEOGEN2	Benign	0.064	.;.;T;.;.;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.44	.;T;.;.;T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0054	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.80	N;N;N;N;.;.;.
REVEL	Benign	0.025
Sift	Benign	1.0	T;T;T;T;.;.;.
Sift4G	Benign	0.38	T;T;T;T;.;.;.
Polyphen		0.0	B;B;B;B;B;B;B
Vest4		0.11
MVP		0.25
MPC		0.12
ClinPred		0.0018	T
GERP RS		-0.073
Varity_R		0.020
gMVP		0.068

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

Publications

LitVar

Other links and lift over

dbSNP: rs117320408; hg19: chr9-79867181;