chr3-165773492-C-T

Position:

chr3-165773492-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000055.4(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).

Frequency

Genomes: 𝑓 0.18 ( 2527 hom., cov: 33)

Exomes 𝑓: 0.20 ( 28481 hom. )

Consequence

BCHE
NM_000055.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:5

Conservation

PhyloP100: 4.44

Variant links:

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]

BCHE links:

BCHE (HGNC:):

BCHE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1699G>A	p.Ala567Thr	missense_variant	4/4	ENST00000264381.8	NP_000046.1	P06276
BCHE	NR_137635.2 linkuse as main transcript	n.292G>A		non_coding_transcript_exon_variant	3/3
BCHE	NR_137636.2 linkuse as main transcript	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 linkuse as main transcript	c.1699G>A	p.Ala567Thr	missense_variant	4/4	1	NM_000055.4	ENSP00000264381.3		P06276

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27788

AN:

151916

Hom.:

2526

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.195

AC XY:

140753

AN XY:

722172

show subpopulations

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.:

AF XY:

0.181

AC XY:

13446

AN XY:

74326

show subpopulations

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:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign: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

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

-0.0063

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.32

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over