rs17228616

chr7-100890100-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
ACHE	NM_000665.5	c.*114C>A		3_prime_UTR_variant	5/5	ENST00000241069.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACHE	ENST00000241069.11	c.*114C>A		3_prime_UTR_variant	5/5	1	NM_000665.5	P1

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

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.0463

Gnomad4 ASJ exome AF: 0.0948

Gnomad4 EAS exome AF: 0.000225

Gnomad4 SAS exome AF: 0.0591

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0394

Gnomad4 OTH exome AF: 0.0571

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

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.0620

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0593

Gnomad4 FIN AF: 0.0293

Gnomad4 NFE AF: 0.0462

Gnomad4 OTH AF: 0.0965

Alfa AF: 0.0567 Hom.: 500

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17228616; hg19: chr7-100487721;