7-100893176-G-T

Position:

chr7-100893176-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000665.5(ACHE):c.1057C>A(p.His353Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,613,808 control chromosomes in the GnomAD database, including 1,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.033 ( 139 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1457 hom. )

Consequence

ACHE
NM_000665.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.51

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026652217).

BP6

Variant 7-100893176-G-T is Benign according to our data. Variant chr7-100893176-G-T is described in ClinVar as [Benign]. Clinvar id is 18335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-100893176-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACHE	NM_000665.5 linkuse as main transcript	c.1057C>A	p.His353Asn	missense_variant	2/5	ENST00000241069.11	NP_000656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACHE	ENST00000241069.11 linkuse as main transcript	c.1057C>A	p.His353Asn	missense_variant	2/5	1	NM_000665.5	ENSP00000241069	P1	P22303-1

Frequencies

GnomAD3 genomes

AF:

0.0327

AC:

4978

AN:

152136

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0361

Gnomad ASJ

AF:

0.0930

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0605

Gnomad FIN

AF:

0.0294

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0455

Gnomad OTH

AF:

0.0532

GnomAD3 exomes

AF:

0.0398

AC:

9934

AN:

249538

Hom.:

282

AF XY:

0.0437

AC XY:

5897

AN XY:

135086

show subpopulations

Gnomad AFR exome

AF:

0.00500

Gnomad AMR exome

AF:

0.0273

Gnomad ASJ exome

AF:

0.0923

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0605

Gnomad FIN exome

AF:

0.0287

Gnomad NFE exome

AF:

0.0463

Gnomad OTH exome

AF:

0.0518

GnomAD4 exome

AF:

0.0396

AC:

57934

AN:

1461554

Hom.:

1457

Cov.:

AF XY:

0.0415

AC XY:

30210

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00577

Gnomad4 AMR exome

AF:

0.0302

Gnomad4 ASJ exome

AF:

0.0923

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0619

Gnomad4 FIN exome

AF:

0.0291

Gnomad4 NFE exome

AF:

0.0396

Gnomad4 OTH exome

AF:

0.0416

GnomAD4 genome

AF:

0.0327

AC:

4973

AN:

152254

Hom.:

139

Cov.:

AF XY:

0.0330

AC XY:

2455

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00616

Gnomad4 AMR

AF:

0.0359

Gnomad4 ASJ

AF:

0.0930

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0603

Gnomad4 FIN

AF:

0.0294

Gnomad4 NFE

AF:

0.0456

Gnomad4 OTH

AF:

0.0522

Alfa

AF:

0.0475

Hom.:

456

Bravo

AF:

0.0314

TwinsUK

AF:

0.0364

AC:

135

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.0473

AC:

407

ExAC

AF:

0.0406

AC:

4935

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0571

EpiControl

AF:

0.0533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

YT BLOOD GROUP POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.13

T;.;T;.;T;T;T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.81

.;T;.;T;T;T;T;.

MetaRNN

Benign

0.0027

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.70

N;N;N;N;N;.;.;N

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

0.17

N;N;N;N;N;N;N;N

REVEL

Benign

0.038

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.048

D;T;D;T;D;.;.;T

Polyphen

0.017

B;B;B;B;B;.;.;B

Vest4

0.12

MPC

0.98

ClinPred

0.011

GERP RS

4.1

Varity_R

0.40

gMVP

0.61

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