9-77228167-G-T

Position:

chr9-77228167-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033305.3(VPS13A):c.1498G>T(p.Val500Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.932

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17247081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VPS13A	NM_033305.3 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/71		NP_001018047.1
VPS13A	NM_015186.4 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/69		NP_056001.1
VPS13A	NM_001018038.3 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/72	1	NM_033305.3	ENSP00000353422	P4	Q96RL7-1
VPS13A	ENST00000376636.7 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/71	1		ENSP00000365823		Q96RL7-3
VPS13A	ENST00000643348.1 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/69			ENSP00000493592		Q96RL7-2
VPS13A	ENST00000645632.1 linkuse as main transcript	c.1498G>T	p.Val500Phe	missense_variant	17/69			ENSP00000496361	A1	Q96RL7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000412

AC:

AN:

242574

Hom.:

AF XY:

0.00000762

AC XY:

AN XY:

131204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

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:

0.00000207

AC:

AN:

1452158

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721904

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000452

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.1498G>T (p.V500F) alteration is located in exon 17 (coding exon 17) of the VPS13A gene. This alteration results from a G to T substitution at nucleotide position 1498, causing the valine (V) at amino acid position 500 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS13A protein function. ClinVar contains an entry for this variant (Variation ID: 1511037). This variant has not been reported in the literature in individuals affected with VPS13A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 500 of the VPS13A protein (p.Val500Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

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

Eigen

Benign

-0.029

Eigen_PC

Benign

0.034

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.89

.;D;.;.;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M;M;M;M;M;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

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

REVEL

Benign

0.046

Sift

Benign

0.073

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

Sift4G

Uncertain

0.026

D;D;D;D;.;.;.

Polyphen

0.66

P;P;P;P;P;P;P

Vest4

0.56

MutPred

0.36

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.65

MPC

0.22

ClinPred

0.24

GERP RS

2.1

Varity_R

0.053

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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