chr3-165773414-T-C

Variant names:

• chr3-165773414-T-C
• rs1038856259
• NM_000055.4:c.1777A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000055.4(BCHE):​c.1777A>G​(p.Thr593Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BCHE NM_000055.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32431358).

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.1777A>G	p.Thr593Ala	missense	Exon 4 of 4	NP_000046.1	P06276
	BCHE	NR_137635.2		n.370A>G		non_coding_transcript_exon	Exon 3 of 3
	BCHE	NR_137636.2		n.1974A>G		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.1777A>G	p.Thr593Ala	missense	Exon 4 of 4	ENSP00000264381.3	P06276
	BCHE	ENST00000479451.5	TSL:1	c.367A>G	p.Thr123Ala	missense	Exon 3 of 3	ENSP00000418325.1	H0Y885
	BCHE	ENST00000855337.1		c.1840A>G	p.Thr614Ala	missense	Exon 5 of 5	ENSP00000525396.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249302 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458738 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725738

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109704

Other (OTH) AF: 0.00 AC: 0 AN: 60240

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.3
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.16
Sift	Benign	0.045	D
Sift4G	Uncertain	0.040	D
Polyphen		0.31	B
Vest4		0.15
MutPred		0.40		Gain of glycosylation at Y592 (P = 0.0507)
MVP		0.81
MPC		0.016
ClinPred		0.21	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.51
Mutation Taster		=71/29	polymorphism

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: rs1038856259; hg19: chr3-165491202;