3-15455920-C-A

Variant names:

• chr3-15455920-C-A
• rs749266800
• NM_005677.4:c.1174G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005677.4(COLQ):​c.1174G>T​(p.Asp392Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D392N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 0 publications found

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]

COLQ Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia

ENSG00000293553 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.21928 (below the threshold of 3.09). Trascript score misZ: -0.17745 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4	c.1174G>T	p.Asp392Tyr	missense_variant	Exon 15 of 17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.1144G>T	p.Asp382Tyr	missense_variant	Exon 15 of 17		NP_536799.1
COLQ	NM_080539.4	c.1072G>T	p.Asp358Tyr	missense_variant	Exon 14 of 16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.1174G>T	p.Asp392Tyr	missense_variant	Exon 15 of 17	1	NM_005677.4	ENSP00000373298.3
COLQ	ENST00000603808.5	c.1174G>T	p.Asp392Tyr	missense_variant	Exon 15 of 17	1		ENSP00000474271.1
ENSG00000293553	ENST00000629729.3	n.21G>T		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000518887.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.17	N
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	1.1	L;.;.;.
PhyloP100		0.10
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.034	D;D;.;.
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		0.99	D;D;.;D
Vest4		0.48
MutPred		0.48		Loss of disorder (P = 0.0199);.;Loss of disorder (P = 0.0199);.;
MVP		0.81
MPC		0.12
ClinPred		0.27	T
GERP RS		-1.8
Varity_R		0.077
gMVP		0.68
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs749266800; hg19: chr3-15497427;