Genetic Variant ACHE:p.Pro477Pro (chr7-100892456-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000665.5(ACHE):c.1431C>T(p.Pro477Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 1,559,426 control chromosomes in the GnomAD database, including 3,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 1412 hom., cov: 30)

Exomes 𝑓: 0.046 ( 2526 hom. )

Consequence

ACHE
NM_000665.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0170

Publications

40 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACHE	NM_000665.5 link	c.1431C>T	p.Pro477Pro	synonymous_variant	Exon 3 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.1431C>T	p.Pro477Pro	synonymous_variant	Exon 3 of 5	1	NM_000665.5	ENSP00000241069.5		P22303-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15232

AN:

149882

Hom.:

1409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.00776

Gnomad AMR

AF:

0.0661

Gnomad ASJ

AF:

0.0879

Gnomad EAS

AF:

0.000588

Gnomad SAS

AF:

0.0630

Gnomad FIN

AF:

0.0288

Gnomad MID

AF:

0.103

Gnomad NFE

AF:

0.0460

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.0580

AC:

13155

AN:

226680

AF XY:

0.0568

show subpopulations

Gnomad AFR exome

AF:

0.250

Gnomad AMR exome

AF:

0.0400

Gnomad ASJ exome

AF:

0.0837

Gnomad EAS exome

AF:

0.000339

Gnomad FIN exome

AF:

0.0294

Gnomad NFE exome

AF:

0.0469

Gnomad OTH exome

AF:

0.0603

GnomAD4 exome

AF:

0.0460

AC:

64903

AN:

1409426

Hom.:

2526

Cov.:

AF XY:

0.0469

AC XY:

32537

AN XY:

693058

show subpopulations

African (AFR)

AF:

0.251

AC:

8057

AN:

32134

American (AMR)

AF:

0.0456

AC:

1830

AN:

40114

Ashkenazi Jewish (ASJ)

AF:

0.0845

AC:

1988

AN:

23518

East Asian (EAS)

AF:

0.000284

AC:

AN:

38774

South Asian (SAS)

AF:

0.0616

AC:

4954

AN:

80486

European-Finnish (FIN)

AF:

0.0290

AC:

1506

AN:

51972

Middle Eastern (MID)

AF:

0.115

AC:

637

AN:

5520

European-Non Finnish (NFE)

AF:

0.0394

AC:

42556

AN:

1078922

Other (OTH)

AF:

0.0580

AC:

3364

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3689

7378

11067

14756

18445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1690

3380

5070

6760

8450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.102

AC:

15265

AN:

150000

Hom.:

1412

Cov.:

AF XY:

0.0995

AC XY:

7279

AN XY:

73170

show subpopulations

African (AFR)

AF:

0.247

AC:

10020

AN:

40604

American (AMR)

AF:

0.0657

AC:

984

AN:

14976

Ashkenazi Jewish (ASJ)

AF:

0.0879

AC:

304

AN:

3460

East Asian (EAS)

AF:

0.000589

AC:

AN:

5090

South Asian (SAS)

AF:

0.0627

AC:

295

AN:

4708

European-Finnish (FIN)

AF:

0.0288

AC:

299

AN:

10376

Middle Eastern (MID)

AF:

0.104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0460

AC:

3109

AN:

67554

Other (OTH)

AF:

0.105

AC:

214

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

606

1212

1817

2423

3029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0619

Hom.:

2166

Bravo

AF:

0.110

Asia WGS

AF:

0.0420

AC:

144

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.017

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over