rs865358

Variant names:

• chr3-123700066-G-A
• rs865358
• NM_053025.4:c.3402C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123700066-G-A
• chr3-123700066-G-C
• chr3-123700066-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_053025.4(MYLK):​c.3402C>T​(p.Asn1134Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,613,902 control chromosomes in the GnomAD database, including 789,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68730 hom., cov: 29)
  • Exomes 𝑓: 0.99 (721059 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.47
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-123700066-G-A is Benign according to our data. Variant chr3-123700066-G-A is described in ClinVar as Benign. ClinVar VariationId is 194903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.3402C>T	p.Asn1134Asn	synonymous_variant	Exon 18 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.3402C>T	p.Asn1134Asn	synonymous_variant	Exon 18 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.948 AC: 143999 AN: 151896 Hom.: 68696 Cov.: 29

Gnomad AFR AF: 0.826

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.953

GnomAD2 exomes AF: 0.985 AC: 247623 AN: 251454 AF XY: 0.988

Gnomad AFR exome AF: 0.827

Gnomad AMR exome AF: 0.987

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.987

GnomAD4 exome AF: 0.993 AC: 1451405 AN: 1461888 Hom.: 721059 Cov.: 70 AF XY: 0.993 AC XY: 722475 AN XY: 727246

African (AFR) AF: 0.827 AC: 27684 AN: 33478

American (AMR) AF: 0.984 AC: 44002 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 25715 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 0.998 AC: 86083 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53420 AN: 53420

Middle Eastern (MID) AF: 0.978 AC: 5640 AN: 5768

European-Non Finnish (NFE) AF: 0.998 AC: 1109737 AN: 1112008

Other (OTH) AF: 0.984 AC: 59426 AN: 60396

GnomAD4 genome AF: 0.948 AC: 144087 AN: 152014 Hom.: 68730 Cov.: 29 AF XY: 0.950 AC XY: 70597 AN XY: 74340

African (AFR) AF: 0.826 AC: 34189 AN: 41390

American (AMR) AF: 0.974 AC: 14887 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3427 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5138 AN: 5138

South Asian (SAS) AF: 0.998 AC: 4781 AN: 4792

European-Finnish (FIN) AF: 1.00 AC: 10608 AN: 10608

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67850 AN: 68012

Other (OTH) AF: 0.953 AC: 2011 AN: 2110

Alfa AF: 0.971 Hom.: 47969

Bravo AF: 0.940

Asia WGS AF: 0.989 AC: 3439 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Sep 22, 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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asn1134Asn in exon 18 of MYLK: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 16.5% (728/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs865358). -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 7 Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 11, 2016

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.3402C>T variant affects a conserved nucleotide, resulting in no amino acid change. Mutation Taster predicts the variant is a polymorphism, and 5/5 Alamut algorithms predict no significant effect on splicing. However, these predictions have not been verified with functional studies. This variant is found in 119276/121410 control chromosomes (58732 homozygotes) at a frequency of 0.9824232, which is about 78593 times of maximal expected frequency of a pathogenic allele (0.0000125), suggesting this variant is the ancestral allele and is benign. Taken together, this variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Dec 30, 2014

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. -

Megacystis, microcolon, hypoperistalsis syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

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	-0.49
CADD	Benign	6.2
DANN	Benign	0.67
PhyloP100		2.5
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs865358; hg19: chr3-123418913; COSMIC: COSV108183000; COSMIC: COSV108183000;