NM_005677.4:c.1248C>T

Variant names:

• chr3-15453879-G-A
• rs55866379
• NM_005677.4:c.1248C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005677.4(COLQ):​c.1248C>T​(p.Asp416Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,612,056 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (62 hom., cov: 32)
  • Exomes 𝑓: 0.031 (808 hom.)
• Consequence: COLQ NM_005677.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.50

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:42328): (EAF1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-15453879-G-A is Benign according to our data. Variant chr3-15453879-G-A is described in ClinVar as [Benign]. Clinvar id is 128825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15453879-G-A is described in Lovd as [Likely_benign]. Variant chr3-15453879-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0238 (3619/152214) while in subpopulation NFE AF= 0.0346 (2351/68016). AF 95% confidence interval is 0.0334. There are 62 homozygotes in gnomad4. There are 1737 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4	c.1248C>T	p.Asp416Asp	synonymous_variant	Exon 16 of 17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.1218C>T	p.Asp406Asp	synonymous_variant	Exon 16 of 17		NP_536799.1
COLQ	NM_080539.4	c.1146C>T	p.Asp382Asp	synonymous_variant	Exon 15 of 16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.1248C>T	p.Asp416Asp	synonymous_variant	Exon 16 of 17	1	NM_005677.4	ENSP00000373298.3
COLQ	ENST00000603808.5	c.1251C>T	p.Asp417Asp	synonymous_variant	Exon 16 of 17	1		ENSP00000474271.1
EAF1-AS1	ENST00000629729.2	n.95C>T		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000518887.1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3619 AN: 152096 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00877

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0241 AC: 5975 AN: 247810 Hom.: 86 AF XY: 0.0261 AC XY: 3494 AN XY: 133832

Gnomad AFR exome AF: 0.00842

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0297

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0313 AC: 45629 AN: 1459842 Hom.: 808 Cov.: 32 AF XY: 0.0317 AC XY: 23046 AN XY: 726034

Gnomad4 AFR exome AF: 0.00733

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0314

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0318

GnomAD4 genome AF: 0.0238 AC: 3619 AN: 152214 Hom.: 62 Cov.: 32 AF XY: 0.0233 AC XY: 1737 AN XY: 74412

Gnomad4 AFR AF: 0.00874

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0235

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0287 Hom.: 37

Bravo AF: 0.0243

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jan 10, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 06, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 5 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.57

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: rs55866379; hg19: chr3-15495386;