Variant 10-69162473-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000263559.11(VPS26A):c.619A>G(p.Met207Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS26A
ENST00000263559.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.27

Variant links:

Genes affected

VPS26A (HGNC:12711): (VPS26 retromer complex component A) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

VPS26A links:

VPS26A (HGNC:):

VPS26A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS26A	NM_004896.5 linkuse as main transcript	c.619A>G	p.Met207Val	missense_variant	6/9	ENST00000263559.11	NP_004887.2	O75436-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS26A	ENST00000263559.11 linkuse as main transcript	c.619A>G	p.Met207Val	missense_variant	6/9	1	NM_004896.5	ENSP00000263559.6		O75436-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

243880

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132452

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:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1422028

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709244

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.619A>G (p.M207V) alteration is located in exon 6 (coding exon 6) of the VPS26A gene. This alteration results from a A to G substitution at nucleotide position 619, causing the methionine (M) at amino acid position 207 to be replaced by a valine (V). 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

0.98

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.69

D;.;D;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.6

H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

D;D;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.028

D;D;D;D

Polyphen

0.12

B;.;B;.

Vest4

0.73

MutPred

0.80

Loss of MoRF binding (P = 0.1367);Loss of MoRF binding (P = 0.1367);Loss of MoRF binding (P = 0.1367);.;

MVP

0.53

MPC

0.89

ClinPred

0.99

GERP RS

5.8

Varity_R

0.80

gMVP

0.67

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

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