rs1008156537

Positions:

• chr3-15455932-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005677.4(COLQ):​c.1162G>A​(p.Asp388Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 P:1 U:1
• Conservation: PhyloP100: 7.05

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]

EAF1-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COLQ	NM_005677.4	c.1162G>A	p.Asp388Asn	missense_variant	15/17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.1132G>A	p.Asp378Asn	missense_variant	15/17		NP_536799.1
COLQ	NM_080539.4	c.1060G>A	p.Asp354Asn	missense_variant	14/16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.1162G>A	p.Asp388Asn	missense_variant	15/17	1	NM_005677.4	ENSP00000373298.3
COLQ	ENST00000603808.5	c.1162G>A	p.Asp388Asn	missense_variant	15/17	1		ENSP00000474271.1
EAF1-AS1	ENST00000629729.2	n.9G>A		non_coding_transcript_exon_variant	1/6	5		ENSP00000518887.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251264 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 5 Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	May 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 06, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 388 of the COLQ protein (p.Asp388Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 468340). This variant is also known as p.Asp354Asn. This missense change has been observed in individual(s) with clinical features of COLQ-related conditions (PMID: 31345272). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N;.;N
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.88
MutPred		0.43		Loss of phosphorylation at S391 (P = 0.155);.;Loss of phosphorylation at S391 (P = 0.155);.;
MVP		0.98
MPC		0.095
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.42
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1008156537; hg19: chr3-15497439; COSMIC: COSV67525470; COSMIC: COSV67525470;