chr3-123640516-C-T

Variant names:

• chr3-123640516-C-T
• rs41301337
• NM_053025.4:c.4620-12G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_053025.4(MYLK):​c.4620-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,613,558 control chromosomes in the GnomAD database, including 974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (83 hom., cov: 31)
  • Exomes 𝑓: 0.032 (891 hom.)
• Consequence: MYLK NM_053025.4 intron
• Scores: Splicing: ADA: 0.00001352
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-123640516-C-T is Benign according to our data. Variant chr3-123640516-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123640516-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0293 (4466/152278) while in subpopulation NFE AF= 0.0344 (2341/68014). AF 95% confidence interval is 0.0333. There are 83 homozygotes in gnomad4. There are 2059 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 83 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.4620-12G>A		intron_variant	Intron 27 of 33	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.4620-12G>A		intron_variant	Intron 27 of 33	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4462 AN: 152160 Hom.: 83 Cov.: 31

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0240 AC: 6016 AN: 250630 Hom.: 92 AF XY: 0.0241 AC XY: 3268 AN XY: 135496

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0127

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0336

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.0322 AC: 47125 AN: 1461280 Hom.: 891 Cov.: 32 AF XY: 0.0317 AC XY: 23069 AN XY: 726962

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.0367

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0293 AC: 4466 AN: 152278 Hom.: 83 Cov.: 31 AF XY: 0.0277 AC XY: 2059 AN XY: 74450

Gnomad4 AFR AF: 0.0343

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0310 Hom.: 25

Bravo AF: 0.0291

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Aug 19, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYLK c.4620-12G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.024 in 250630 control chromosomes in the gnomAD database, including 92 homozygotes. The observed variant frequency is approximately 960-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 03, 2016

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. -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 7 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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	-0.89
CADD	Benign	0.32
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs41301337; hg19: chr3-123359363;