7-100893200-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000665.5(ACHE):c.1033G>A(p.Ala345Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACHE NM_000665.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20142111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACHE	NM_000665.5	c.1033G>A	p.Ala345Thr	missense_variant	2/5	ENST00000241069.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACHE	ENST00000241069.11	c.1033G>A	p.Ala345Thr	missense_variant	2/5	1	NM_000665.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ACHE p.Ala345Thr variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB or LOVD 3.0 databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ala345 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;.;T;T;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.24	N;N;N;N;N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.18	N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.63	T;T;T;T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T;.;.;T
Polyphen		0.72	P;P;P;P;P;.;.;P
Vest4		0.12
MutPred		0.33		Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);Loss of stability (P = 0.0827);
MVP		0.70
MPC		1.2
ClinPred		0.54	D
GERP RS		4.9
Varity_R		0.17
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-100490821;