rs201376373

Variant names:

• chr3-15521514-A-G
• rs201376373
• NM_005677.4:c.106+6T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005677.4(COLQ):​c.106+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,130 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: COLQ NM_005677.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001462
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.01
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-15521514-A-G is Benign according to our data. Variant chr3-15521514-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287047.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (177/152284) while in subpopulation NFE AF = 0.0021 (143/68030). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	NM_005677.4	MANE Select	c.106+6T>C		splice_region intron	N/A	NP_005668.2
	COLQ	NM_080539.4		c.106+6T>C		splice_region intron	N/A	NP_536800.2	Q9Y215-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	ENST00000383788.10	TSL:1 MANE Select	c.106+6T>C		splice_region intron	N/A	ENSP00000373298.3	Q9Y215-1
	COLQ	ENST00000603808.5	TSL:1	c.106+6T>C		splice_region intron	N/A	ENSP00000474271.1	A0A0C4DGS2
	COLQ	ENST00000874202.1		c.106+6T>C		splice_region intron	N/A	ENSP00000544261.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00100 AC: 252 AN: 251418 AF XY: 0.00102

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000972

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00164 AC: 2395 AN: 1461846 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 1173 AN XY: 727224

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86258

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53382

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

European-Non Finnish (NFE) AF: 0.00199 AC: 2218 AN: 1112004

Other (OTH) AF: 0.00132 AC: 80 AN: 60394

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74466

African (AFR) AF: 0.000168 AC: 7 AN: 41558

American (AMR) AF: 0.000916 AC: 14 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.00117

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Congenital myasthenic syndrome 5 (2)
-	-	1	COLQ-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.077
DANN	Benign	0.34
PhyloP100		-1.0
PromoterAI		-0.039	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.070
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201376373;

hg19: chr3-15563021;