ENST00000302913.8:c.1795C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000302913.8(ACHE):c.1795C>A(p.Pro599Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,456,298 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 29 hom. )

Consequence

ACHE
ENST00000302913.8 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0510

Variant links:

Genes affected

ACHE (HGNC:108): (acetylcholinesterase (Yt blood group)) Acetylcholinesterase hydrolyzes the neurotransmitter, acetylcholine at neuromuscular junctions and brain cholinergic synapses, and thus terminates signal transmission. It is also found on the red blood cell membranes, where it constitutes the Yt blood group antigen. Acetylcholinesterase exists in multiple molecular forms which possess similar catalytic properties, but differ in their oligomeric assembly and mode of cell attachment to the cell surface. It is encoded by the single ACHE gene, and the structural diversity in the gene products arises from alternative mRNA splicing, and post-translational associations of catalytic and structural subunits. The major form of acetylcholinesterase found in brain, muscle and other tissues is the hydrophilic species, which forms disulfide-linked oligomers with collagenous, or lipid-containing structural subunits. The other, alternatively spliced form, expressed primarily in the erythroid tissues, differs at the C-terminal end, and contains a cleavable hydrophobic peptide with a GPI-anchor site. It associates with the membranes through the phosphoinositide (PI) moieties added post-translationally. AChE activity may constitute a sensitive biomarker of RBC ageing in vivo, and thus, may be of aid in understanding the effects of transfusion[provided by RefSeq, Sep 2019]

ACHE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062592626).

BP6

Variant 7-100891017-G-T is Benign according to our data. Variant chr7-100891017-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3042137.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 29 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACHE	NM_000665.5 link	c.1723+152C>A		intron_variant	Intron 4 of 4	ENST00000241069.11	NP_000656.1	P22303-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACHE	ENST00000241069.11 link	c.1723+152C>A		intron_variant	Intron 4 of 4	1	NM_000665.5	ENSP00000241069.5		P22303-1

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

627

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00600

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00433

AC:

362

AN:

83660

Hom.:

AF XY:

0.00442

AC XY:

188

AN XY:

42500

show subpopulations

Gnomad AFR exome

AF:

0.000583

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00303

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.00807

Gnomad NFE exome

AF:

0.00588

Gnomad OTH exome

AF:

0.00737

GnomAD4 exome

AF:

0.00582

AC:

7583

AN:

1303936

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

3562

AN XY:

632682

show subpopulations

Gnomad4 AFR exome

AF:

0.00112

Gnomad4 AMR exome

AF:

0.00288

Gnomad4 ASJ exome

AF:

0.00294

Gnomad4 EAS exome

AF:

0.0000289

Gnomad4 SAS exome

AF:

0.00316

Gnomad4 FIN exome

AF:

0.00809

Gnomad4 NFE exome

AF:

0.00633

Gnomad4 OTH exome

AF:

0.00540

GnomAD4 genome

AF:

0.00412

AC:

627

AN:

152362

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

290

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.00600

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00463

Hom.:

Bravo

AF:

0.00413

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00264

AC:

ExAC

AF:

0.00267

AC:

294

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACHE-related disorder

Benign:1

Nov 16, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.2

DANN

Benign

0.75

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.46

T;.

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.46

PROVEAN

Benign

0.73

N;N

REVEL

Benign

0.020

Sift

Benign

0.42

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.29

B;B

Vest4

0.18

MVP

0.51

MPC

0.96

ClinPred

0.00021

GERP RS

-0.10

gMVP

0.61

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