rs1799805

Variant names:

• chr7-100893176-G-T
• rs1799805
• NM_000665.5:c.1057C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (139 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1457 hom.)
• Consequence: ACHE NM_000665.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.51
• Publications: 39 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 18335.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000665.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACHE	NM_000665.5	MANE Select	c.1057C>A	p.His353Asn	missense	Exon 2 of 5	NP_000656.1	P22303-1
	ACHE	NM_001367918.1		c.1258C>A	p.His420Asn	missense	Exon 2 of 5	NP_001354847.1
	ACHE	NM_001367919.2		c.1255C>A	p.His419Asn	missense	Exon 2 of 5	NP_001354848.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACHE	ENST00000241069.11	TSL:1 MANE Select	c.1057C>A	p.His353Asn	missense	Exon 2 of 5	ENSP00000241069.5	P22303-1
	ACHE	ENST00000302913.8	TSL:1	c.1057C>A	p.His353Asn	missense	Exon 2 of 5	ENSP00000303211.4	P22303-2
	ACHE	ENST00000411582.4	TSL:1	c.1057C>A	p.His353Asn	missense	Exon 2 of 5	ENSP00000404865.1	P22303-2

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

GnomAD2 exomes AF: 0.0398 AC: 9934 AN: 249538 AF XY: 0.0437

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 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

African (AFR) AF: 0.00577 AC: 193 AN: 33474

American (AMR) AF: 0.0302 AC: 1348 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0923 AC: 2410 AN: 26120

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39696

South Asian (SAS) AF: 0.0619 AC: 5335 AN: 86228

European-Finnish (FIN) AF: 0.0291 AC: 1549 AN: 53280

Middle Eastern (MID) AF: 0.101 AC: 583 AN: 5768

European-Non Finnish (NFE) AF: 0.0396 AC: 43993 AN: 1111896

Other (OTH) AF: 0.0416 AC: 2512 AN: 60386

GnomAD4 genome AF: 0.0327 AC: 4973 AN: 152254 Hom.: 139 Cov.: 32 AF XY: 0.0330 AC XY: 2455 AN XY: 74446

African (AFR) AF: 0.00616 AC: 256 AN: 41544

American (AMR) AF: 0.0359 AC: 550 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0930 AC: 323 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4826

European-Finnish (FIN) AF: 0.0294 AC: 312 AN: 10618

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3098 AN: 68002

Other (OTH) AF: 0.0522 AC: 110 AN: 2108

Alfa AF: 0.0446 Hom.: 608

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	YT BLOOD GROUP POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.70	N
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.038
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.048	D
Polyphen		0.017	B
Vest4		0.12
MPC		0.98
ClinPred		0.011	T
GERP RS		4.1
Varity_R		0.40
gMVP		0.61
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

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