3-123612296-T-C

Variant names:

• chr3-123612296-T-C
• rs6438804
• NM_053025.4:c.*1809A>G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.*1809A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,564 control chromosomes in the GnomAD database, including 10,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (10377 hom., cov: 32)
  • Exomes 𝑓: 0.087 (1 hom.)
• Consequence: MYLK NM_053025.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.266

Genes affected

MYLK (HGNC:7590): (myosin light chain kinase) This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-123612296-T-C is Benign according to our data. Variant chr3-123612296-T-C is described in ClinVar as [Benign]. Clinvar id is 342823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.*1809A>G		3_prime_UTR_variant	Exon 34 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304	c.*1809A>G		3_prime_UTR_variant	Exon 34 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46110 AN: 152008 Hom.: 10345 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.0931

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.0868 AC: 38 AN: 438 Hom.: 1 Cov.: 0 AF XY: 0.106 AC XY: 28 AN XY: 264

Gnomad4 AFR exome AF: 1.00

Gnomad4 FIN exome AF: 0.0845

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.304 AC: 46200 AN: 152126 Hom.: 10377 Cov.: 32 AF XY: 0.304 AC XY: 22592 AN XY: 74376

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.0931

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.294

Alfa AF: 0.185 Hom.: 5540

Bravo AF: 0.336

Asia WGS AF: 0.450 AC: 1566 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 7 Benign:2

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. -

Jul 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	3.7
DANN	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6438804; hg19: chr3-123331143; COSMIC: COSV60607056; COSMIC: COSV60607056;