rs28933389

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000055.4(BCHE):c.812C>T(p.Thr271Met) variant causes a missense change. The variant allele was found at a frequency of 0.000747 in 1,613,898 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T271T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

BCHE
NM_000055.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.87

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-165830222-G-A is Pathogenic according to our data. Variant chr3-165830222-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13218.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BCHE	NM_000055.4 linkuse as main transcript	c.812C>T	p.Thr271Met	missense_variant	2/4	ENST00000264381.8
BCHE	NR_137636.2 linkuse as main transcript	n.930C>T		non_coding_transcript_exon_variant	2/5
BCHE	NR_137635.2 linkuse as main transcript	n.110+7092C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCHE	ENST00000264381.8 linkuse as main transcript	c.812C>T	p.Thr271Met	missense_variant	2/4	1	NM_000055.4	P1
LINC01322	ENST00000651449.1 linkuse as main transcript	n.1008-15670G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000439

AC:

110

AN:

250754

Hom.:

AF XY:

0.000450

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000733

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000764

AC:

1117

AN:

1461678

Hom.:

Cov.:

AF XY:

0.000743

AC XY:

540

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000942

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000585

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000868

Hom.:

Bravo

AF:

0.000642

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000928

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of butyrylcholinesterase

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	Variant summary: BCHE c.812C>T (p.Thr271Met, legacy name Thr243Met or the flu-1 allele) results in a non-conservative amino acid change located in the Carboxylesterase, type B domain (IPR002018) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 250754 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency of butyrylcholine esterase (0.00044 vs 0.016), allowing no conclusion about variant significance. c.812C>T has been reported in the literature among compound heterozygous individuals affected with a deficiency of butyrylcholine esterase manifesting as the fluoride-resistant phenotype (example, Nogueira_1992, Yen_2003 and LaDu_1990). It has subsequently been cited in the literature (example, LaDu_1991 and Lando_2003). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although a decrease in the number of carbohydrate chains per subunit, from nine to eight, has been attributed to the loss of Threonine residue in this variant (Nogueira_1992). The following publications have been ascertained in the context of this evaluation (PMID: 2013061, 2253336, 12724618, 1415224, 12881446, 33010031). ClinVar contains an entry for this variant (Variation ID: 13218). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 10, 2019	The BCHE c.812C>T (p.Thr271Met) missense variant, also known as p.Thr243Met, is one of two known fluoride-resistant variants that affect sensitivity to succinylcholine. This variant has been reported in at least three studies and was found in a total of five probands, including in four in a compound heterozygous state, two of whom were related, and in one in a heterozygous state (Nogueira et al. 1992; Lando et al. 2003; Yen et al. 2003). Two additional related individuals with this variant were also reported by La Du et al. (1990). Control data are not available for this variant, which is reported at a frequency of 0.00091 in the African American population of the Exome Sequencing Project. The p.Thr271Met variant affects a glycosylation site on the BCHE protein, reducing the number of carbohydrate chains attached to the mature protein (Nogueira et al. 1992). Based on the evidence, the p.Thr271Met variant is classified as likely pathogenic for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

BCHE, flouride 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1992

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2020

Classified by the PharmGKB project as a polymorphism associated with prolonged apnea, with alternate names listed as F-Variant, BCHE*243M, and Thr243Met (Alvarellos et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 2253336, 1415224, 11928765, 13711731, 15563885, 12724618, 2013061, 26398623, 12881446, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Uncertain

0.11

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.59

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.89

Vest4

0.65

MVP

1.0

MPC

0.052

ClinPred

0.063

GERP RS

5.6

Varity_R

0.77

gMVP

0.70

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