rs113607507

Variant names:

• chr3-123640510-G-A
• rs113607507
• NM_053025.4:c.4620-6C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_053025.4(MYLK):​c.4620-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,804 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: MYLK NM_053025.4 splice_region, intron
• Scores: Splicing: ADA: 0.002411
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.683
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 3-123640510-G-A is Benign according to our data. Variant chr3-123640510-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227625.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00188 (286/152288) while in subpopulation AMR AF = 0.00372 (57/15306). AF 95% confidence interval is 0.00295. There are 0 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.4620-6C>T		splice_region_variant, 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.4620-6C>T		splice_region_variant, intron_variant	Intron 27 of 33	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00184 AC: 461 AN: 250856 AF XY: 0.00179

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00182 AC: 2661 AN: 1461516 Hom.: 7 Cov.: 32 AF XY: 0.00183 AC XY: 1332 AN XY: 727068

African (AFR) AF: 0.000448 AC: 15 AN: 33470

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86250

European-Finnish (FIN) AF: 0.00116 AC: 62 AN: 53406

Middle Eastern (MID) AF: 0.00788 AC: 43 AN: 5458

European-Non Finnish (NFE) AF: 0.00194 AC: 2155 AN: 1112010

Other (OTH) AF: 0.00215 AC: 130 AN: 60364

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74470

African (AFR) AF: 0.000265 AC: 11 AN: 41570

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00273 AC: 186 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00243 Hom.: 4

Bravo AF: 0.00193

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYLK: BP4, BS2 -

Aug 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 15, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 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.4620-6C>T 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 0.0018 in 250856 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 73.5 fold the estimated maximal allele frequency expected for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4620-6C>T in individuals affected with Aortopathy and no experimental evidence demonstrating an impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 4/5 laboratories cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Nov 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4620-6C>T in intron 27 of MYLK: This variant is not expected to have clinical significance because a C>T change at this position does not diverge from the spl ice consensus sequence and is therefore unlikely to impact splicing. It has also been identified in 0.23% (155/66614) of European chromosomes and 0.22% (25/1156 2) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs113607507). -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 7 Uncertain:1 Benign: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. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Apr 05, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.2
DANN	Benign	0.86
PhyloP100		0.68
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.042
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: rs113607507; hg19: chr3-123359357;