rs139444683

Positions:

chr9-77221345-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_033305.3(VPS13A):c.1150G>A(p.Val384Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,598 control chromosomes in the GnomAD database, including 1 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. V384V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.21

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014962941).

BP6

Variant 9-77221345-G-A is Benign according to our data. Variant chr9-77221345-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586927.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VPS13A	NM_033305.3 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/72	ENST00000360280.8
VPS13A	NM_001018037.2 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/71
VPS13A	NM_015186.4 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/69
VPS13A	NM_001018038.3 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/72	1	NM_033305.3	P4	Q96RL7-1
VPS13A	ENST00000376636.7 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/71	1			Q96RL7-3
VPS13A	ENST00000643348.1 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/69				Q96RL7-2
VPS13A	ENST00000645632.1 linkuse as main transcript	c.1150G>A	p.Val384Met	missense_variant	13/69			A1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250682

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1460408

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726492

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000112

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 10, 2018

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

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

0.076

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.14

.;.;T;.;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.55

.;T;.;.;T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.015

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;N;N;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.48

N;N;N;N;.;.;.

REVEL

Benign

0.035

Sift

Benign

0.18

T;T;T;T;.;.;.

Sift4G

Benign

0.086

T;T;T;T;.;.;.

Polyphen

0.0040

B;B;B;B;B;B;B

Vest4

0.15

MVP

0.11

MPC

0.13

ClinPred

0.015

GERP RS

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.030

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over