chr3-123692775-G-A

Variant names:

• chr3-123692775-G-A
• rs147735490
• NM_053025.4:c.3525C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_053025.4(MYLK):​c.3525C>T​(p.Asp1175Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,614,024 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (19 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -1.44
• Publications: 3 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)

LOC105369194 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-123692775-G-A is Benign according to our data. Variant chr3-123692775-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226763.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000591 (90/152246) while in subpopulation SAS AF = 0.0114 (55/4810). AF 95% confidence interval is 0.00902. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.3525C>T	p.Asp1175Asp	synonymous	Exon 19 of 34	NP_444253.3
	MYLK	NM_053027.4		c.3525C>T	p.Asp1175Asp	synonymous	Exon 19 of 33	NP_444255.3
	MYLK	NM_053026.4		c.3318C>T	p.Asp1106Asp	synonymous	Exon 18 of 33	NP_444254.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.3525C>T	p.Asp1175Asp	synonymous	Exon 19 of 34	ENSP00000353452.3
	MYLK	ENST00000504946.6	TSL:1	c.1134C>T	p.Asp378Asp	synonymous	Exon 3 of 4	ENSP00000510315.1
	MYLK	ENST00000464489.5	TSL:1	n.*3104C>T		non_coding_transcript_exon	Exon 18 of 33	ENSP00000417798.1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00166 AC: 418 AN: 251340 AF XY: 0.00221

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000861 AC: 1258 AN: 1461778 Hom.: 19 Cov.: 33 AF XY: 0.00119 AC XY: 866 AN XY: 727190

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.000730 AC: 29 AN: 39700

South Asian (SAS) AF: 0.0113 AC: 974 AN: 86258

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53330

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5764

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111990

Other (OTH) AF: 0.00111 AC: 67 AN: 60396

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74426

African (AFR) AF: 0.000193 AC: 8 AN: 41556

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4810

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000283

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2017

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.

Apr 19, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp1175Asp in exon 19 of MYLK: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 1.1% (184/16510) of South Asian chromosomes including 3 homozygous individuals by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs147735490).

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:2

Nov 02, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not provided Benign:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYLK: BP4, BP7, BS1, BS2

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aortic aneurysm, familial thoracic 7 Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.92
PhyloP100		-1.4
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147735490; hg19: chr3-123411622; COSMIC: COSV60608032; COSMIC: COSV60608032;