7-100892509-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000665.5(ACHE):c.1378G>A(p.Val460Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,601,366 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: ACHE NM_000665.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.51

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036664963).
• BP6: Variant 7-100892509-C-T is Benign according to our data. Variant chr7-100892509-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2358297.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACHE	NM_000665.5	c.1378G>A	p.Val460Ile	missense_variant	3/5	ENST00000241069.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACHE	ENST00000241069.11	c.1378G>A	p.Val460Ile	missense_variant	3/5	1	NM_000665.5	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151770 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000125 AC: 31 AN: 248378 Hom.: 0 AF XY: 0.000149 AC XY: 20 AN XY: 134326

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000683 AC: 99 AN: 1449478 Hom.: 0 Cov.: 32 AF XY: 0.0000752 AC XY: 54 AN XY: 718292

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000662

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151888 Hom.: 0 Cov.: 31 AF XY: 0.000189 AC XY: 14 AN XY: 74252

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.0000958 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.000297

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	1.2
Dann	Benign	0.94
DEOGEN2	Benign	0.14	T;.;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.037	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.22	N;N;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.18	T;T;T;T;T;T
Sift4G	Benign	0.092	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.030
MVP		0.32
MPC		0.70
ClinPred		0.0076	T
GERP RS		-4.3
Varity_R		0.32
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs546907479; hg19: chr7-100490130;