chr9-77293357-G-A

Position:

chr9-77293357-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033305.3(VPS13A):c.3356G>A(p.Gly1119Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,612,310 control chromosomes in the GnomAD database, including 26 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 24 hom. )

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.46

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:

VPS13A (HGNC:):

VPS13A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006241679).

BP6

Variant 9-77293357-G-A is Benign according to our data. Variant chr9-77293357-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77293357-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00214 (325/152190) while in subpopulation NFE AF= 0.00231 (157/68008). AF 95% confidence interval is 0.00201. There are 2 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3 linkuse as main transcript	c.3356G>A	p.Gly1119Glu	missense_variant	32/72	ENST00000360280.8	NP_150648.2	Q96RL7-1
VPS13A	NM_001018037.2 linkuse as main transcript	c.3239G>A	p.Gly1080Glu	missense_variant	31/71		NP_001018047.1	Q96RL7-3
VPS13A	NM_015186.4 linkuse as main transcript	c.3356G>A	p.Gly1119Glu	missense_variant	32/69		NP_056001.1	Q96RL7-2
VPS13A	NM_001018038.3 linkuse as main transcript	c.3356G>A	p.Gly1119Glu	missense_variant	32/69		NP_001018048.1	Q96RL7-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8 linkuse as main transcript	c.3356G>A	p.Gly1119Glu	missense_variant	32/72	1	NM_033305.3	ENSP00000353422.3		Q96RL7-1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00310

AC:

776

AN:

250496

Hom.:

AF XY:

0.00303

AC XY:

410

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00128

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.00640

GnomAD4 exome

AF:

0.00255

AC:

3723

AN:

1460120

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

1888

AN XY:

726380

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

Gnomad4 AMR exome

AF:

0.00245

Gnomad4 ASJ exome

AF:

0.0236

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00230

Gnomad4 OTH exome

AF:

0.00400

GnomAD4 genome

AF:

0.00214

AC:

325

AN:

152190

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00293

Hom.:

Bravo

AF:

0.00242

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00301

AC:

366

Asia WGS

AF:

0.00145

AC:

AN:

3474

EpiCase

AF:

0.00236

EpiControl

AF:

0.00481

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2019	This variant is associated with the following publications: (PMID: 26870756) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	VPS13A: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Chorea-acanthocytosis

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

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

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.050

MetaRNN

Benign

0.0062

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

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.9

M;.;M;M;M;M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

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

REVEL

Benign

0.13

Sift

Benign

0.069

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

Sift4G

Benign

0.11

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

Polyphen

0.66

P;P;B;P;P;P;B

Vest4

0.32

MVP

0.67

MPC

0.20

ClinPred

0.051

GERP RS

3.6

Varity_R

0.27

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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