Variant 1-12234357-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_015378.4(VPS13D):c.91C>T(p.Leu31Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

VPS13D
NM_015378.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

VPS13D (HGNC:23595): (vacuolar protein sorting 13 homolog D) This gene encodes a protein belonging to the vacuolar-protein-sorting-13 gene family. In yeast, vacuolar-protein-sorting-13 proteins are involved in trafficking of membrane proteins between the trans-Golgi network and the prevacuolar compartment. While several transcript variants may exist for this gene, the full-length natures of only two have been described to date. These two represent the major variants of this gene and encode distinct isoforms. [provided by RefSeq, Jul 2008]

VPS13D links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VPS13D. . Trascript score misZ 4.4951 (greater than threshold 3.09). GenCC has associacion of gene with Leigh syndrome, autosomal recessive cerebellar ataxia-saccadic intrusion syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.35410988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13D	NM_015378.4 linkuse as main transcript	c.91C>T	p.Leu31Phe	missense_variant	2/70	ENST00000620676.6	NP_056193.2
VPS13D	NM_018156.4 linkuse as main transcript	c.91C>T	p.Leu31Phe	missense_variant	2/69		NP_060626.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13D	ENST00000620676.6 linkuse as main transcript	c.91C>T	p.Leu31Phe	missense_variant	2/70	1	NM_015378.4	ENSP00000478104	P3	Q5THJ4-1
VPS13D	ENST00000613099.4 linkuse as main transcript	c.91C>T	p.Leu31Phe	missense_variant	2/69	1		ENSP00000482233	A1	Q5THJ4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251000

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135670

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726862

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.91C>T (p.L31F) alteration is located in exon 2 (coding exon 1) of the VPS13D gene. This alteration results from a C to T substitution at nucleotide position 91, causing the leucine (L) at amino acid position 31 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.56

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

0.025

MutationAssessor

Benign

0.76

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

Sift4G

Uncertain

0.018

D;D

Polyphen

0.93

P;P

Vest4

0.56

MutPred

0.42

Gain of catalytic residue at L31 (P = 0.047);Gain of catalytic residue at L31 (P = 0.047);

MVP

0.043

ClinPred

0.76

GERP RS

3.6

Varity_R

0.62

gMVP

0.51

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