3-15456013-G-C

Position:

• chr3-15456013-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005677.4(COLQ):​c.1081C>G​(p.Pro361Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P361S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COLQ	NM_005677.4	c.1081C>G	p.Pro361Ala	missense_variant	15/17	ENST00000383788.10
COLQ	NM_080538.2	c.1051C>G	p.Pro351Ala	missense_variant	15/17
COLQ	NM_080539.4	c.979C>G	p.Pro327Ala	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COLQ	ENST00000383788.10	c.1081C>G	p.Pro361Ala	missense_variant	15/17	1	NM_005677.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0050	D;D;.;.
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.98	D;D;.;D
Vest4		0.83
MutPred		0.54		Gain of catalytic residue at P361 (P = 0.0118);.;Gain of catalytic residue at P361 (P = 0.0118);.;
MVP		0.98
MPC		0.094
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.60

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: rs116828761; hg19: chr3-15497520;