rs750387

Positions:

• chr3-15479331-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005677.4(COLQ):​c.366+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,613,144 control chromosomes in the GnomAD database, including 1,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (178 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1025 hom.)
• Consequence: COLQ NM_005677.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006183
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.315

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-15479331-T-C is Benign according to our data. Variant chr3-15479331-T-C is described in ClinVar as [Benign]. Clinvar id is 128826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15479331-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COLQ	NM_005677.4	c.366+7A>G		splice_region_variant, intron_variant		ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.336+7A>G		splice_region_variant, intron_variant			NP_536799.1
COLQ	NM_080539.4	c.264+7A>G		splice_region_variant, intron_variant			NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.366+7A>G		splice_region_variant, intron_variant		1	NM_005677.4	ENSP00000373298	P4

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6413 AN: 152148 Hom.: 178 Cov.: 32

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0545

GnomAD3 exomes AF: 0.0308 AC: 7745 AN: 251466 Hom.: 166 AF XY: 0.0317 AC XY: 4309 AN XY: 135906

Gnomad AFR exome AF: 0.0623

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0313

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0356 AC: 51939 AN: 1460878 Hom.: 1025 Cov.: 31 AF XY: 0.0360 AC XY: 26131 AN XY: 726844

Gnomad4 AFR exome AF: 0.0656

Gnomad4 AMR exome AF: 0.0238

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0328

Gnomad4 FIN exome AF: 0.0170

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0404

GnomAD4 genome AF: 0.0422 AC: 6420 AN: 152266 Hom.: 178 Cov.: 32 AF XY: 0.0404 AC XY: 3012 AN XY: 74474

Gnomad4 AFR AF: 0.0644

Gnomad4 AMR AF: 0.0407

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0379

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0398 Hom.: 173

Bravo AF: 0.0444

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0422

EpiControl AF: 0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2020	- -

Congenital myasthenic syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.11		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: rs750387; hg19: chr3-15520838;