Variant 7-100891327-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000665.5(ACHE):c.1565A>C(p.Glu522Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,402,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ACHE
NM_000665.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14166534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACHE	NM_000665.5 link	c.1565A>C	p.Glu522Ala	missense_variant	Exon 4 of 5	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.1565A>C	p.Glu522Ala	missense_variant	Exon 4 of 5	1	NM_000665.5	ENSP00000241069.5		P22303-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402522

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693540

show subpopulations

Gnomad4 AFR exome

AF:

0.0000321

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1565A>C (p.E522A) alteration is located in exon 4 (coding exon 3) of the ACHE gene. This alteration results from a A to C substitution at nucleotide position 1565, causing the glutamic acid (E) at amino acid position 522 to be replaced by an alanine (A). 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

Benign

0.097

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.15

T;.;T;.;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

.;T;.;T;T;.

M_CAP

Benign

0.079

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.23

N;.;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.83

N;N;N;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.67

T;T;T;T;T;T

Sift4G

Benign

0.74

T;T;T;T;T;T

Polyphen

0.018

B;B;B;B;B;B

Vest4

0.22

MutPred

0.36

Gain of MoRF binding (P = 0.0499);.;Gain of MoRF binding (P = 0.0499);Gain of MoRF binding (P = 0.0499);Gain of MoRF binding (P = 0.0499);Gain of MoRF binding (P = 0.0499);

MVP

0.47

MPC

0.92

ClinPred

0.21

GERP RS

4.2

Varity_R

0.54

gMVP

0.47

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over