rs398124632

Variant names:

• chr3-165830599-A-CT
• rs398124632
• NM_000055.4:c.435delTinsAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000055.4(BCHE):​c.435delTinsAG​(p.Phe146ValfsTer12) variant causes a frameshift, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G145G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCHE NM_000055.4 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.0470
• Publications: 4 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-165830599-A-CT is Pathogenic according to our data. Variant chr3-165830599-A-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 13216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.435delTinsAG	p.Phe146ValfsTer12	frameshift synonymous	Exon 2 of 4	NP_000046.1	P06276
	BCHE	NR_137636.2		n.553delTinsAG		non_coding_transcript_exon	Exon 2 of 5
	BCHE	NR_137635.2		n.110+6715delTinsAG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCHE	ENST00000264381.8	TSL:1 MANE Select	c.435delTinsAG	p.Phe146ValfsTer12	frameshift synonymous	Exon 2 of 4	ENSP00000264381.3	P06276
	BCHE	ENST00000479451.5	TSL:1	c.107+6715delTinsAG		intron	N/A	ENSP00000418325.1	H0Y885
	BCHE	ENST00000855337.1		c.435delTinsAG	p.Phe146ValfsTer12	frameshift synonymous	Exon 2 of 5	ENSP00000525396.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Deficiency of butyrylcholinesterase (4)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.047
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398124632; hg19: chr3-165548387;