rs121918557

Positions:

• chr3-165829962-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000055.4(BCHE):​c.1072T>A​(p.Leu358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 1.47

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-165829962-A-T is Pathogenic according to our data. Variant chr3-165829962-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26669723). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCHE	NM_000055.4	c.1072T>A	p.Leu358Ile	missense_variant	2/4	ENST00000264381.8
BCHE	NR_137636.2	n.1190T>A		non_coding_transcript_exon_variant	2/5
BCHE	NR_137635.2	n.110+7352T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCHE	ENST00000264381.8	c.1072T>A	p.Leu358Ile	missense_variant	2/4	1	NM_000055.4	P1
LINC01322	ENST00000651449.1	n.1008-15930A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000882 AC: 22 AN: 249532 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.0000880 AC XY: 64 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyrylcholinesterase Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 05, 2017	The BCHE c.1072T>A (p.Leu358Ile) missense variant, also known as p.Leu330Ile, has been reported in at least five studies and is found in a total of 15 individuals with butyrylcholinesterase deficiency, including in two in a homozygous state, in two in a compound heterozygous state, and in eleven in a heterozygous state (Iida et al. 1995; Maekawa et al. 1997; Sudo et al. 1997; Asanuma et al. 1999; Liu et al. 2002). Ten of the 11 heterozygous individuals had a moderate reduction of their serum cholinesterase activity, in contrast to the two homozygous and the two compound heterozygous individuals, who all had a severe reduction of their serum cholinesterase activity. Control data are unavailable for this variant, which is reported at a frequency of 0.00106 in the East Asian population of the Genome Aggregation Database. Expression in HEK293 cells revealed that p.Leu358Ile variant had 20% residual serum cholinesterase activity compared to wild type (Liu et al. 2002). Based on the collective evidence, the p.Leu358Ile variant is classified as pathogenic for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Feb 27, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2022	Variant summary: BCHE c.1072T>A (p.Leu358Ile) results in a conservative amino acid change located in the Carboxylesterase, type B of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 249532 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (8.8e-05 vs 0.016), allowing no conclusion about variant significance. c.1072T>A has been reported in the literature in individuals affected with Deficiency Of Butyrylcholine Esterase (e.g. Iida_1995, Sudo_1997, Liu_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Sudo_1997, Liu_2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Butyrylcholinesterase deficiency, fluoride-resistant, Japanese type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 17, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.85	L
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.36
Sift	Benign	0.39	T
Sift4G	Benign	0.46	T
Polyphen		0.65	P
Vest4		0.65
MVP		0.88
MPC		0.079
ClinPred		0.15	T
GERP RS		0.18
Varity_R		0.46
gMVP		0.38

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: rs121918557; hg19: chr3-165547750;