rs113607507

Positions:

• chr3-123640510-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002411
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.683

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 -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 id is 227625.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=1}. Variant chr3-123640510-G-A is described in Lovd as [Likely_benign]. Variant chr3-123640510-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00182 (2661/1461516) while in subpopulation MID AF= 0.00788 (43/5458). AF 95% confidence interval is 0.00601. There are 7 homozygotes in gnomad4_exome. There are 1332 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4	c.4620-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.4620-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_053025.4	ENSP00000353452	P4
MYLK-AS1	ENST00000485162.5	n.523-3994G>A		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes AF: 0.00184 AC: 461 AN: 250856 Hom.: 3 AF XY: 0.00179 AC XY: 243 AN XY: 135588

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 SAS exome AF: 0.000425

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

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00215

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

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00271 Hom.: 0

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYLK: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 10, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2019	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. -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.2
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs113607507; hg19: chr3-123359357;