NM_033305.3:c.8225A>G

Variant names:

• chr9-77365473-A-G
• rs145686832
• NM_033305.3:c.8225A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033305.3(VPS13A):​c.8225A>G​(p.His2742Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000554 in 1,607,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.68

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020935118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.8108A>G	p.His2703Arg	missense_variant	Exon 59 of 71		NP_001018047.1
VPS13A	NM_015186.4	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69		NP_056001.1
VPS13A	NM_001018038.3	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.8108A>G	p.His2703Arg	missense_variant	Exon 59 of 71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.8225A>G	p.His2742Arg	missense_variant	Exon 60 of 69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000679 AC: 17 AN: 250430 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135490

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000344 AC: 50 AN: 1455492 Hom.: 0 Cov.: 29 AF XY: 0.0000331 AC XY: 24 AN XY: 724556

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0000448

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: 0.00000723

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74444

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000463 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Aug 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2742 of the VPS13A protein (p.His2742Arg). This variant is present in population databases (rs145686832, gnomAD 0.1%). 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: 448872). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VPS13A protein function with a negative predictive value of 80%. 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

Nov 23, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chorea-acanthocytosis Uncertain:1

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.055
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.13	.;.;T;.;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	.;T;.;.;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.021	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.57	N;.;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.19	N;N;N;N;.;.;.
REVEL	Benign	0.024
Sift	Benign	0.15	T;T;T;T;.;.;.
Sift4G	Benign	0.17	T;T;T;T;.;.;.
Polyphen		0.031	B;B;B;B;B;B;B
Vest4		0.29
MVP		0.46
MPC		0.16
ClinPred		0.095	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.099
gMVP		0.17

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: rs145686832; hg19: chr9-79980389;