7-100891017-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (29 hom.)
• Consequence: ACHE ENST00000302913.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510

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]

ACMG classification

Verdict is Benign. Variant got -10 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 criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACHE	NM_000665.5	c.1723+152C>A		intron_variant		ENST00000241069.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACHE	ENST00000241069.11	c.1723+152C>A		intron_variant		1	NM_000665.5	P1

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152244 Hom.: 1 Cov.: 33

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.: 2 AF XY: 0.00442 AC XY: 188 AN XY: 42500

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.: 29 Cov.: 31 AF XY: 0.00563 AC XY: 3562 AN XY: 632682

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.: 1 Cov.: 33 AF XY: 0.00389 AC XY: 290 AN XY: 74510

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.: 2

Bravo AF: 0.00413

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00264 AC: 21

ExAC AF: 0.00267 AC: 294

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ACHE-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2021

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	T
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	N
LIST_S2	Benign	0.46	T;.
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs17886728; hg19: chr7-100488638;