3-123640516-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 262284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• 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

GnomAD2 exomes AF: 0.0240 AC: 6016 AN: 250630 AF XY: 0.0241

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 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

African (AFR) AF: 0.0356 AC: 1192 AN: 33456

American (AMR) AF: 0.0113 AC: 504 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 429 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0124 AC: 1068 AN: 86232

European-Finnish (FIN) AF: 0.0257 AC: 1370 AN: 53408

Middle Eastern (MID) AF: 0.0118 AC: 63 AN: 5318

European-Non Finnish (NFE) AF: 0.0367 AC: 40783 AN: 1111970

Other (OTH) AF: 0.0284 AC: 1713 AN: 60336

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

African (AFR) AF: 0.0343 AC: 1425 AN: 41574

American (AMR) AF: 0.0137 AC: 209 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4826

European-Finnish (FIN) AF: 0.0285 AC: 302 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0344 AC: 2341 AN: 68014

Other (OTH) AF: 0.0232 AC: 49 AN: 2116

Alfa AF: 0.0313 Hom.: 49

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

-

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

- -

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. -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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, University Medical Center Utrecht

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

-

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
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41301337; hg19: chr3-123359363;