NM_005677.4:c.1120A>C

Variant names:

• chr3-15455974-T-G
• rs1553634628
• NM_005677.4:c.1120A>C

Variant summary

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

The NM_005677.4(COLQ):​c.1120A>C​(p.Thr374Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.261
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005677.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	NM_005677.4	MANE Select	c.1120A>C	p.Thr374Pro	missense	Exon 15 of 17	NP_005668.2
	COLQ	NM_080538.2		c.1090A>C	p.Thr364Pro	missense	Exon 15 of 17	NP_536799.1
	COLQ	NM_080539.4		c.1018A>C	p.Thr340Pro	missense	Exon 14 of 16	NP_536800.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	ENST00000383788.10	TSL:1 MANE Select	c.1120A>C	p.Thr374Pro	missense	Exon 15 of 17	ENSP00000373298.3
	COLQ	ENST00000603808.5	TSL:1	c.1120A>C	p.Thr374Pro	missense	Exon 15 of 17	ENSP00000474271.1
	COLQ	ENST00000383781.8	TSL:5	c.1090A>C	p.Thr364Pro	missense	Exon 15 of 17	ENSP00000373291.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 5 Uncertain:1

Aug 11, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.26
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.50
Sift	Benign	0.064	T
Sift4G	Benign	0.20	T
Polyphen		0.86	P
Vest4		0.39
MutPred		0.47		Loss of glycosylation at T374 (P = 0.052)
MVP		0.96
MPC		0.13
ClinPred		0.24	T
GERP RS		1.7
Varity_R		0.24
gMVP		0.63
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1553634628; hg19: chr3-15497481;