rs17228616

Variant names:

• chr7-100890100-G-T
• rs17228616
• NM_000665.5:c.*114C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000665.5(ACHE):​c.*114C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 1,339,558 control chromosomes in the GnomAD database, including 3,218 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 0.095 (1230 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1988 hom.)
• Consequence: ACHE NM_000665.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.112
• Publications: 27 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACHE	NM_000665.5	c.*114C>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000241069.11	NP_000656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACHE	ENST00000241069.11	c.*114C>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_000665.5	ENSP00000241069.5

Frequencies

GnomAD3 genomes AF: 0.0952 AC: 14486 AN: 152148 Hom.: 1225 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0622

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0980

GnomAD4 exome AF: 0.0455 AC: 54013 AN: 1187292 Hom.: 1988 Cov.: 16 AF XY: 0.0463 AC XY: 26999 AN XY: 583424

African (AFR) AF: 0.227 AC: 6308 AN: 27744

American (AMR) AF: 0.0463 AC: 1399 AN: 30210

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 1818 AN: 19172

East Asian (EAS) AF: 0.000225 AC: 8 AN: 35488

South Asian (SAS) AF: 0.0591 AC: 3844 AN: 65064

European-Finnish (FIN) AF: 0.0299 AC: 1040 AN: 34766

Middle Eastern (MID) AF: 0.120 AC: 416 AN: 3454

European-Non Finnish (NFE) AF: 0.0394 AC: 36318 AN: 921294

Other (OTH) AF: 0.0571 AC: 2862 AN: 50100

GnomAD4 genome AF: 0.0954 AC: 14519 AN: 152266 Hom.: 1230 Cov.: 32 AF XY: 0.0928 AC XY: 6909 AN XY: 74468

African (AFR) AF: 0.223 AC: 9243 AN: 41524

American (AMR) AF: 0.0620 AC: 948 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0593 AC: 286 AN: 4824

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10624

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0462 AC: 3145 AN: 68016

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.0662 Hom.: 1187

Bravo AF: 0.103

Asia WGS AF: 0.0400 AC: 138 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.8
DANN	Benign	0.71
PhyloP100		-0.11
PromoterAI		0.055	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17228616; hg19: chr7-100487721;