rs1803274

Positions:

• chr3-165773492-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000264381.8(BCHE):​c.1699G>A​(p.Ala567Thr) variant causes a missense change. The variant allele was found at a frequency of 0.194 in 1,602,676 control chromosomes in the GnomAD database, including 31,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A567V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2527 hom., cov: 33)
  • Exomes 𝑓: 0.20 (28481 hom.)
• Consequence: BCHE ENST00000264381.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:5
• Conservation: PhyloP100: 4.44

Genes affected

BCHE (HGNC:983): (butyrylcholinesterase) This gene encodes a cholinesterase enzyme and member of the type-B carboxylesterase/lipase family of proteins. The encoded enzyme exhibits broad substrate specificity and is involved in the detoxification of poisons including organophosphate nerve agents and pesticides, and the metabolism of drugs including cocaine, heroin and aspirin. Humans homozygous for certain mutations in this gene exhibit prolonged apnea after administration of the muscle relaxant succinylcholine. [provided by RefSeq, Jul 2016]

LINC01322 (HGNC:50528): (long intergenic non-protein coding RNA 1322)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018072128).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCHE	NM_000055.4	c.1699G>A	p.Ala567Thr	missense_variant	4/4	ENST00000264381.8	NP_000046.1
BCHE	NR_137635.2	n.292G>A		non_coding_transcript_exon_variant	3/3
BCHE	NR_137636.2	n.1896G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8	c.1699G>A	p.Ala567Thr	missense_variant	4/4	1	NM_000055.4	ENSP00000264381	P1
LINC01322	ENST00000651449.1	n.1008-72400C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27788 AN: 151916 Hom.: 2526 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.176 AC: 43392 AN: 246726 Hom.: 4056 AF XY: 0.180 AC XY: 23963 AN XY: 133496

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.195 AC: 283194 AN: 1450642 Hom.: 28481 Cov.: 31 AF XY: 0.195 AC XY: 140753 AN XY: 722172

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.195

GnomAD4 genome AF: 0.183 AC: 27789 AN: 152034 Hom.: 2527 Cov.: 33 AF XY: 0.181 AC XY: 13446 AN XY: 74326

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.184

Alfa AF: 0.197 Hom.: 4105

Bravo AF: 0.185

TwinsUK AF: 0.206 AC: 763

ALSPAC AF: 0.199 AC: 767

ESP6500AA AF: 0.190 AC: 835

ESP6500EA AF: 0.202 AC: 1735

ExAC AF: 0.181 AC: 21914

Asia WGS AF: 0.142 AC: 496 AN: 3468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2021	See Variant Classification Assertion Criteria. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 15, 2023

Variant summary: BCHE c.1699G>A (p.Ala567Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.18 in 246726 control chromosomes in the gnomAD database, including 4056 homozygotes. The observed variant frequency is approximately 11.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase phenotype (0.016), indicating the variant is benign. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as benign while one classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -

Deficiency of butyrylcholinesterase Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Butyrylcholinesterase activity Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.0063
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.93	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.14
Sift	Benign	0.093	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0010	B;.
Vest4		0.036
MPC		0.015
ClinPred		0.021	T
GERP RS		4.1
Varity_R		0.22
gMVP		0.26

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: rs1803274; hg19: chr3-165491280; COSMIC: COSV52256958; COSMIC: COSV52256958;