rs142980906

Positions:

• chr3-15478979-T-A
• chr3-15478979-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_005677.4(COLQ):​c.391A>T​(p.Lys131Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COLQ NM_005677.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9684
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72

Genes affected

COLQ (HGNC:2226): (collagen like tail subunit of asymmetric acetylcholinesterase) This gene encodes the subunit of a collagen-like molecule associated with acetylcholinesterase in skeletal muscle. Each molecule is composed of three identical subunits. Each subunit contains a proline-rich attachment domain (PRAD) that binds an acetylcholinesterase tetramer to anchor the catalytic subunit of the enzyme to the basal lamina. Mutations in this gene are associated with endplate acetylcholinesterase deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COLQ	NM_005677.4	c.391A>T	p.Lys131Ter	stop_gained, splice_region_variant	5/17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.361A>T	p.Lys121Ter	stop_gained, splice_region_variant	5/17		NP_536799.1
COLQ	NM_080539.4	c.289A>T	p.Lys97Ter	stop_gained, splice_region_variant	4/16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.391A>T	p.Lys131Ter	stop_gained, splice_region_variant	5/17	1	NM_005677.4	ENSP00000373298	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	63
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;D
Vest4		0.86
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: 2
DS_DL_spliceai		0.61		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs142980906; hg19: chr3-15520486;