3-165773492-C-T

Variant names:

• chr3-165773492-C-T
• rs1803274
• NM_000055.4:c.1699G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A567V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2527 hom., cov: 33)
  • Exomes 𝑓: 0.20 (28481 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:6
• Conservation: PhyloP100: 4.44
• Publications: 122 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000055.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCHE	NM_000055.4	MANE Select	c.1699G>A	p.Ala567Thr	missense	Exon 4 of 4	NP_000046.1	P06276
	BCHE	NR_137635.2		n.292G>A		non_coding_transcript_exon	Exon 3 of 3
	BCHE	NR_137636.2		n.1896G>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCHE	ENST00000264381.8	TSL:1 MANE Select	c.1699G>A	p.Ala567Thr	missense	Exon 4 of 4	ENSP00000264381.3	P06276
	BCHE	ENST00000479451.5	TSL:1	c.289G>A	p.Ala97Thr	missense	Exon 3 of 3	ENSP00000418325.1	H0Y885
	BCHE	ENST00000855337.1		c.1762G>A	p.Ala588Thr	missense	Exon 5 of 5	ENSP00000525396.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27788 AN: 151916 Hom.: 2526 Cov.: 33

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

GnomAD2 exomes AF: 0.176 AC: 43392 AN: 246726 AF XY: 0.180

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 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.: 31 AF XY: 0.195 AC XY: 140753 AN XY: 722172

African (AFR) AF: 0.192 AC: 6373 AN: 33210

American (AMR) AF: 0.118 AC: 5240 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4629 AN: 26016

East Asian (EAS) AF: 0.139 AC: 5479 AN: 39480

South Asian (SAS) AF: 0.187 AC: 16036 AN: 85868

European-Finnish (FIN) AF: 0.169 AC: 9003 AN: 53256

Middle Eastern (MID) AF: 0.230 AC: 1320 AN: 5738

European-Non Finnish (NFE) AF: 0.203 AC: 223431 AN: 1102434

Other (OTH) AF: 0.195 AC: 11683 AN: 60052

GnomAD4 genome AF: 0.183 AC: 27789 AN: 152034 Hom.: 2527 Cov.: 33 AF XY: 0.181 AC XY: 13446 AN XY: 74326

African (AFR) AF: 0.189 AC: 7823 AN: 41476

American (AMR) AF: 0.138 AC: 2111 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3466

East Asian (EAS) AF: 0.117 AC: 607 AN: 5174

South Asian (SAS) AF: 0.168 AC: 809 AN: 4824

European-Finnish (FIN) AF: 0.165 AC: 1747 AN: 10568

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13441 AN: 67946

Other (OTH) AF: 0.184 AC: 388 AN: 2114

Alfa AF: 0.193 Hom.: 5508

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Butyrylcholinesterase activity (1)
-	-	1	Deficiency of butyrylcholinesterase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.0063
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.14
Sift	Benign	0.093	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.036
MPC		0.015
ClinPred		0.021	T
GERP RS		4.1
Varity_R		0.22
gMVP		0.26
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1803274; hg19: chr3-165491280; COSMIC: COSV52256958; COSMIC: COSV52256958;