rs1799807

Variant names:

• chr3-165830741-T-C
• rs1799807
• NM_000055.4:c.293A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-165830741-T-C
• chr3-165830741-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_000055.4(BCHE):​c.293A>G​(p.Asp98Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,613,944 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000967600: "In vitro functional studies provide evidence that the p.Asp98Gly variant impacts BCHE enzyme activity." PMID:9047329, PMID:27551784" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (228 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 B:1 O:3
• Conservation: PhyloP100: 7.23
• Publications: 130 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000967600: "In vitro functional studies provide evidence that the p.Asp98Gly variant impacts BCHE enzyme activity." PMID:9047329, PMID:27551784; SCV001370742: Experimental evidence evaluating an impact on protein function demonstrated the variant negatively affects enzyme activity and concentration, causing a reduction in substrate affinity and an abolition of substrate activation (e.g. Delacour_2014, Lockridge_2016, Masson_1999).; SCV004046421: Functional studies suggest the c.293A>G (p.Asp98Gly) variant leads to reduced enzyme activity and binding affinity for succinylcholine (PMID: 25448037, 2915989).; SCV002004685: Published functional studies demonstrate a severe reduction in affinity for butyrylthiocholine and succinyldithiocholine (PMID: 9047329, 23123771); SCV003799857: Functional studies show the variant causes reduced enzyme activity and a reduction in substrate affinity/activation (Delacour 2014, Lockridge 2016, Masson 1999). PMID: 25054547 PMID: 27551784 PMID: 10446378
• PP5: Variant 3-165830741-T-C is Pathogenic according to our data. Variant chr3-165830741-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13215.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006447643). . Strength limited to SUPPORTING due to the PP5.

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.293A>G	p.Asp98Gly	missense	Exon 2 of 4	NP_000046.1	P06276
	BCHE	NR_137636.2		n.411A>G		non_coding_transcript_exon	Exon 2 of 5
	BCHE	NR_137635.2		n.110+6573A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCHE	ENST00000264381.8	TSL:1 MANE Select	c.293A>G	p.Asp98Gly	missense	Exon 2 of 4	ENSP00000264381.3	P06276
	BCHE	ENST00000479451.5	TSL:1	c.107+6573A>G		intron	N/A	ENSP00000418325.1	H0Y885
	BCHE	ENST00000855337.1		c.293A>G	p.Asp98Gly	missense	Exon 2 of 5	ENSP00000525396.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 152168 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0121 AC: 3044 AN: 250996 AF XY: 0.0125

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00905

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0164 AC: 23967 AN: 1461658 Hom.: 228 Cov.: 32 AF XY: 0.0161 AC XY: 11725 AN XY: 727124

African (AFR) AF: 0.00293 AC: 98 AN: 33442

American (AMR) AF: 0.00922 AC: 412 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 432 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00363 AC: 313 AN: 86250

European-Finnish (FIN) AF: 0.0115 AC: 614 AN: 53410

Middle Eastern (MID) AF: 0.0257 AC: 148 AN: 5766

European-Non Finnish (NFE) AF: 0.0190 AC: 21079 AN: 1111918

Other (OTH) AF: 0.0144 AC: 869 AN: 60386

GnomAD4 genome AF: 0.0124 AC: 1894 AN: 152286 Hom.: 18 Cov.: 32 AF XY: 0.0121 AC XY: 901 AN XY: 74468

African (AFR) AF: 0.00363 AC: 151 AN: 41570

American (AMR) AF: 0.0131 AC: 200 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1269 AN: 68018

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0162 Hom.: 93

Bravo AF: 0.0124

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0199 AC: 171

ExAC AF: 0.0121 AC: 1465

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0211

EpiControl AF: 0.0195

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
12	-	-	Deficiency of butyrylcholinesterase (15)
7	-	1	not provided (8)
1	-	-	BCHE-related disorder (1)
1	-	-	Postanesthetic apnea (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.0050	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.69	P
Vest4		0.27
MPC		0.11
ClinPred		0.062	T
GERP RS		5.8
Varity_R		0.92
gMVP		0.74
Mutation Taster		=74/26	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1799807; hg19: chr3-165548529;