Genetic Variant NM_033305.3:c.2748A>T (chr9-77276145-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033305.3(VPS13A):c.2748A>T(p.Glu916Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E916A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

VPS13A
NM_033305.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.637

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

chorea-acanthocytosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

VPS13A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09266704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VPS13A	NM_033305.3 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 71		NP_001018047.1
VPS13A	NM_015186.4 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 69		NP_056001.1
VPS13A	NM_001018038.3 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VPS13A	ENST00000360280.8 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 69			ENSP00000493592.1
VPS13A	ENST00000645632.1 link	c.2748A>T	p.Glu916Asp	missense_variant	Exon 26 of 69			ENSP00000496361.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

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

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.72

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

M_CAP

Benign

0.0037

MetaRNN

Benign

0.093

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

L;L;L;L;L;L;L

PhyloP100

0.64

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

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

REVEL

Benign

0.10

Sift

Benign

0.14

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

Sift4G

Benign

0.11

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

Polyphen

0.075

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

Vest4

0.15

MutPred

0.49

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);

MVP

0.39

MPC

0.12

ClinPred

0.12

GERP RS

-5.0

Varity_R

0.049

gMVP

0.68

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over