chr3-165786245-A-T

Position:

chr3-165786245-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_000055.4(BCHE):c.1584T>A(p.Tyr528*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BCHE
NM_000055.4 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.643

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 Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.124 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-165786245-A-T is Pathogenic according to our data. Variant chr3-165786245-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555346.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCHE	NM_000055.4 linkuse as main transcript	c.1584T>A	p.Tyr528*	stop_gained	3/4	ENST00000264381.8	NP_000046.1	P06276
BCHE	NR_137635.2 linkuse as main transcript	n.177T>A		non_coding_transcript_exon_variant	2/3
BCHE	NR_137636.2 linkuse as main transcript	n.1702T>A		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.1584T>A	p.Tyr528*	stop_gained	3/4	1	NM_000055.4	ENSP00000264381.3		P06276

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250512

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000435

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460296

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726474

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000403

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151848

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

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:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 28, 2024	Variant summary: BCHE c.1584T>A (p.Tyr528X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 6.4e-05 in 250512 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (6.4e-05 vs 0.016), allowing no conclusion about variant significance. c.1584T>A has been reported in the literature in an individual affected with Deficiency Of Butyrylcholine Esterase who was compound heterozygous with another pathogenic variant (Primo-Parmo_1996). The following publication has been ascertained in the context of this evaluation (PMID: 8554068). ClinVar contains an entry for this variant (Variation ID: 555346). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The BCHE c.1584T>A (p.Tyr528Ter) stop-gained variant, also referred to as BCHE*500STOP, has been reported in a compound heterozygous state with a frameshift variant in one individual who was described as having sensitivity to succinylcholine and showed no BCHE protein activity in a plasma sample (Primo-Parmo et al. 1996). Control data are unavailable for this variant, which is reported at a frequency of 0.00018 in the Latino population of the Exome Aggregation Consortium, but this is based on two alleles so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Tyr528Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for butyrylcholinesterase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.20

Eigen_PC

Benign

-0.0024

FATHMM_MKL

Benign

0.64

Vest4

0.99

GERP RS

0.57

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