chr3-15451237-G-A

Variant names:

• chr3-15451237-G-A
• rs569980572
• NM_005677.4:c.*407C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005677.4(COLQ):​c.*407C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 273,670 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00092 (4 hom.)
• Consequence: COLQ NM_005677.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.78

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000381 (58/152152) while in subpopulation SAS AF= 0.00417 (20/4794). AF 95% confidence interval is 0.00276. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4	c.*407C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.*407C>T		3_prime_UTR_variant	Exon 17 of 17		NP_536799.1
COLQ	NM_080539.4	c.*407C>T		3_prime_UTR_variant	Exon 16 of 16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788	c.*407C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_005677.4	ENSP00000373298.3
EAF1-AS1	ENST00000629729.2	n.414+208C>T		intron_variant	Intron 3 of 5	5		ENSP00000518887.1
COLQ	ENST00000603808.5	c.*407C>T		downstream_gene_variant		1		ENSP00000474271.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00438

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000922 AC: 112 AN: 121518 Hom.: 4 Cov.: 0 AF XY: 0.00131 AC XY: 84 AN XY: 64102

Gnomad4 AFR exome AF: 0.000440

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00492

Gnomad4 FIN exome AF: 0.000180

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.000635

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74396

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000272

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 5 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.71

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: rs569980572; hg19: chr3-15492744;