7-100896377-T-G

Variant names:

• chr7-100896377-T-G
• rs3757869
• ENST00000445236.3:c.-21+176A>C

Variant summary

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

The NM_001367918.1(ACHE):​c.178+176A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 157,828 control chromosomes in the GnomAD database, including 23,214 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 0.54 (22357 hom., cov: 31)
  • Exomes 𝑓: 0.51 (857 hom.)
• Consequence: ACHE NM_001367918.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.826
• Publications: 8 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367918.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACHE	NM_001367918.1		c.178+176A>C		intron	N/A	NP_001354847.1
	ACHE	NM_001367919.2		c.178+176A>C		intron	N/A	NP_001354848.1
	ACHE	NR_160407.1		n.442+176A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACHE	ENST00000445236.3	TSL:1	c.-21+176A>C		intron	N/A	ENSP00000400933.3
	ACHE	ENST00000894905.1		c.-144A>C		5_prime_UTR	Exon 2 of 6	ENSP00000564964.1
	ACHE	ENST00000894903.1		c.-21+3A>C		splice_region intron	N/A	ENSP00000564962.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81382 AN: 151622 Hom.: 22335 Cov.: 31

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.835

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.568

GnomAD4 exome AF: 0.510 AC: 3107 AN: 6088 Hom.: 857 Cov.: 0 AF XY: 0.526 AC XY: 2041 AN XY: 3878

African (AFR) AF: 0.318 AC: 7 AN: 22

American (AMR) AF: 0.628 AC: 54 AN: 86

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 50 AN: 108

East Asian (EAS) AF: 0.729 AC: 35 AN: 48

South Asian (SAS) AF: 0.563 AC: 1286 AN: 2284

European-Finnish (FIN) AF: 0.487 AC: 253 AN: 520

Middle Eastern (MID) AF: 0.438 AC: 7 AN: 16

European-Non Finnish (NFE) AF: 0.469 AC: 1308 AN: 2790

Other (OTH) AF: 0.500 AC: 107 AN: 214

GnomAD4 genome AF: 0.537 AC: 81455 AN: 151740 Hom.: 22357 Cov.: 31 AF XY: 0.543 AC XY: 40239 AN XY: 74156

African (AFR) AF: 0.486 AC: 20091 AN: 41362

American (AMR) AF: 0.653 AC: 9972 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1990 AN: 3468

East Asian (EAS) AF: 0.834 AC: 4256 AN: 5102

South Asian (SAS) AF: 0.595 AC: 2859 AN: 4804

European-Finnish (FIN) AF: 0.517 AC: 5452 AN: 10540

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34926 AN: 67888

Other (OTH) AF: 0.569 AC: 1197 AN: 2104

Alfa AF: 0.526 Hom.: 20283

Bravo AF: 0.547

Asia WGS AF: 0.696 AC: 2419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.5
DANN	Benign	0.47
PhyloP100		0.83
PromoterAI		0.0073	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3757869; hg19: chr7-100493998;