rs1799805

chr7-100893176-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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 (no stars). 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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.51

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 -13 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 no_assertion_criteria_provided, 0 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	UniProt
ACHE	NM_000665.5	c.1057C>A	p.His353Asn	missense_variant	2/5	ENST00000241069.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACHE	ENST00000241069.11	c.1057C>A	p.His353Asn	missense_variant	2/5	1	NM_000665.5	P1

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4978 AN: 152136 Hom.: 139 Cov.: 32

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

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.: 32 AF XY: 0.0415 AC XY: 30210 AN XY: 727082

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.: 32 AF XY: 0.0330 AC XY: 2455 AN XY: 74446

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: 29

ESP6500EA AF: 0.0473 AC: 407

ExAC AF: 0.0406 AC: 4935

Asia WGS AF: 0.0270 AC: 93 AN: 3478

EpiCase AF: 0.0571

EpiControl AF: 0.0533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

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	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
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	N
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.70	N;N;N;N;N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs1799805; hg19: chr7-100490797; COSMIC: COSV53816386; COSMIC: COSV53816386;