rs121918556

Positions:

chr3-165786255-T-A

Variant summary

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

The NM_000055.4(BCHE):c.1574A>T(p.Glu525Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,612,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

BCHE
NM_000055.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.60

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:

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

LINC01322 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BCHE	NM_000055.4 linkuse as main transcript	c.1574A>T	p.Glu525Val	missense_variant	3/4	ENST00000264381.8	NP_000046.1
BCHE	NR_137635.2 linkuse as main transcript	n.167A>T		non_coding_transcript_exon_variant	2/3
BCHE	NR_137636.2 linkuse as main transcript	n.1692A>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8 linkuse as main transcript	c.1574A>T	p.Glu525Val	missense_variant	3/4	1	NM_000055.4	ENSP00000264381	P1
LINC01322	ENST00000651449.1 linkuse as main transcript	n.1008-59637T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250396

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460242

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726436

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000848

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

BCHE, J variant

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1992

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 18, 2023

Variant summary: BCHE c.1574A>T (p.Glu525Val), also referred to in the literature as the J-variant mutation, results in a non-conservative amino acid change located in the carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1574A>T has been reported in the literature, in cis with a common benign variant (c.1699G>A, p.Ala567Thr), in the heterozygous state and in the compound heterozygous state in trans with a pathogenic variant (c.293A>G, p.Asp98Gly) in multiple individuals from a multi-generational kindred undergoing testing for decreased serum butyrylcholinesterase activity (Garry_1976, Bartels_1992). Individuals who were compound heterozygous with the pathogenic variant tended to have a decreased enzyme activity in comparison to those who were heterozygous carriers of the variant of interest, however, it was not clear whether these individuals exhibited a clinical phenotype of Deficiency Of Butyrylcholine Esterase (Bartels_1992). Based on genotype-phenotype comparisons within individuals in this kindred, it was estimated that the variant allele was associated with a decrease of 66-72% from the wild type activity (Bartels_1992), but to our knowledge, the effect of this variant has yet to be tested in functional studies or studied without the c.1699G>A, p.Ala567Thr variant in cis. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Deficiency Of Butyrylcholine Esterase. The following publications have been ascertained in the context of this evaluation (PMID: 1349196, 1271425). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

D;D;D

Eigen

Benign

-0.10

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

1.7

L;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.60

Sift

Benign

0.17

T;D;D

Sift4G

Benign

0.23

T;D;D

Polyphen

0.0030

B;.;.

Vest4

0.58

MVP

0.99

MPC

0.015

ClinPred

0.57

GERP RS

5.5

Varity_R

0.57

gMVP

0.59

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

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