rs541051874

Positions:

chr9-77220298-C-T

Variant summary

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

The NM_033305.3(VPS13A):c.904C>T(p.Leu302Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,611,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.12

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=0.25796804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VPS13A	ENST00000360280.8 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/72	1	NM_033305.3	ENSP00000353422.3	Q96RL7-1
VPS13A	ENST00000376636.7 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/71	1		ENSP00000365823.3	Q96RL7-3
VPS13A	ENST00000643348.1 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/69			ENSP00000493592.1	Q96RL7-2
VPS13A	ENST00000645632.1 linkuse as main transcript	c.904C>T	p.Leu302Phe	missense_variant	12/69			ENSP00000496361.1	Q96RL7-4

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151724

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249876

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000987

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1460050

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726278

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151824

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

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

Jul 09, 2024

The c.904C>T (p.L302F) alteration is located in exon 12 (coding exon 12) of the VPS13A gene. This alteration results from a C to T substitution at nucleotide position 904, causing the leucine (L) at amino acid position 302 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Chorea-acanthocytosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.025

MetaRNN

Benign

0.26

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

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.1

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

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

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

REVEL

Benign

0.29

Sift

Benign

0.038

D;D;T;D;.;.;.

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

D;D;D;D;D;D;D

Vest4

0.51

MutPred

0.47

Loss of catalytic residue at M299 (P = 0.0695);Loss of catalytic residue at M299 (P = 0.0695);Loss of catalytic residue at M299 (P = 0.0695);Loss of catalytic residue at M299 (P = 0.0695);Loss of catalytic residue at M299 (P = 0.0695);Loss of catalytic residue at M299 (P = 0.0695);Loss of catalytic residue at M299 (P = 0.0695);

MVP

0.61

MPC

0.57

ClinPred

0.96

GERP RS

4.8

Varity_R

0.70

gMVP

0.65

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