chr3-165773388-AC-A

Variant names:

• chr3-165773388-AC-A
• rs535319263
• NM_000055.4:c.1802delG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_Moderate BS2_Supporting

The NM_000055.4(BCHE):​c.1802delG​(p.Gly601ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000658 in 1,610,698 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (2 hom.)
• Consequence: BCHE NM_000055.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.384

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 Uncertain_significance. Variant got 1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00387 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCHE	NM_000055.4	c.1802delG	p.Gly601ValfsTer4	frameshift_variant	Exon 4 of 4	ENST00000264381.8	NP_000046.1
BCHE	NR_137635.2	n.395delG		non_coding_transcript_exon_variant	Exon 3 of 3
BCHE	NR_137636.2	n.1999delG		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCHE	ENST00000264381.8	c.1802delG	p.Gly601ValfsTer4	frameshift_variant	Exon 4 of 4	1	NM_000055.4	ENSP00000264381.3

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000161 AC: 40 AN: 249108 Hom.: 1 AF XY: 0.000163 AC XY: 22 AN XY: 134638

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000686 AC: 100 AN: 1458492 Hom.: 2 Cov.: 30 AF XY: 0.0000992 AC XY: 72 AN XY: 725636

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000999

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74412

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BCHE c.1802delG (p.Gly601ValfsX4) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.00016 in 249108 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in BCHE causing Deficiency Of Butyrylcholine Esterase (0.00016 vs 0.016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1802delG in individuals affected with Deficiency Of Butyrylcholine Esterase and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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: rs535319263; hg19: chr3-165491176;