rs139574075

Variant names:

• chr3-15453899-G-A
• rs139574075
• NM_005677.4:c.1228C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-15453899-G-A
• chr3-15453899-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_005677.4(COLQ):​c.1228C>T​(p.Arg410Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,068 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R410Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.62
• Publications: 6 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)

ENSG00000293553 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_005677.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15453898-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 938138.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.21928 (below the threshold of 3.09). Trascript score misZ: -0.17745 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 5.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant 3-15453899-G-A is Pathogenic according to our data. Variant chr3-15453899-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 381725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1228C>T	p.Arg410Trp	missense	Exon 16 of 17	NP_005668.2
	COLQ	NM_080538.2		c.1198C>T	p.Arg400Trp	missense	Exon 16 of 17	NP_536799.1	Q9Y215-2
	COLQ	NM_080539.4		c.1126C>T	p.Arg376Trp	missense	Exon 15 of 16	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.1228C>T	p.Arg410Trp	missense	Exon 16 of 17	ENSP00000373298.3	Q9Y215-1
	COLQ	ENST00000603808.5	TSL:1	c.1231C>T	p.Arg411Trp	missense	Exon 16 of 17	ENSP00000474271.1	A0A0C4DGS2
	ENSG00000293553	ENST00000629729.3	TSL:5	n.75C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000518887.1	A0AAA9YHP9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000285 AC: 7 AN: 245856 AF XY: 0.0000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1458878 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 725424

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.0000449 AC: 2 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39524

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1110596

Other (OTH) AF: 0.0000498 AC: 3 AN: 60286

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74396

African (AFR) AF: 0.0000241 AC: 1 AN: 41528

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Congenital myasthenic syndrome 5 (5)
1	-	-	Congenital myasthenic syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.6
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.72
MVP		1.0
MPC		0.10
ClinPred		0.73	D
GERP RS		4.1
Varity_R		0.21
gMVP		0.76
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139574075; hg19: chr3-15495406;