chr3-15455974-T-G

Position:

• chr3-15455974-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COLQ	NM_005677.4	c.1120A>C	p.Thr374Pro	missense_variant	15/17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.1090A>C	p.Thr364Pro	missense_variant	15/17		NP_536799.1
COLQ	NM_080539.4	c.1018A>C	p.Thr340Pro	missense_variant	14/16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.1120A>C	p.Thr374Pro	missense_variant	15/17	1	NM_005677.4	ENSP00000373298.3
COLQ	ENST00000603808.5	c.1120A>C	p.Thr374Pro	missense_variant	15/17	1		ENSP00000474271.1
EAF1-AS1	ENST00000629729.2	n.-34A>C		upstream_gene_variant		5		ENSP00000518887.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

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;D;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.0	L;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N;N;.;N
REVEL	Uncertain	0.50
Sift	Benign	0.064	T;D;.;.
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.86	P;D;.;P
Vest4		0.39
MutPred		0.47		Loss of glycosylation at T374 (P = 0.052);.;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

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: rs1553634628; hg19: chr3-15497481;