3-123700066-G-A

Position:

• chr3-123700066-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_053025.4(MYLK):​c.3402C>T​(p.Asn1134=) 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

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]

LOC105369194 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 194903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700066-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
MYLK	NM_053025.4	c.3402C>T	p.Asn1134=	synonymous_variant	18/34	ENST00000360304.8	NP_444253.3
LOC105369194	XR_924417.4	n.108-3800G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.3402C>T	p.Asn1134=	synonymous_variant	18/34	5	NM_053025.4	ENSP00000353452	P4

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

GnomAD3 exomes AF: 0.985 AC: 247623 AN: 251454 Hom.: 122159 AF XY: 0.988 AC XY: 134289 AN XY: 135896

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 SAS exome AF: 0.998

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

Gnomad4 AFR exome AF: 0.827

Gnomad4 AMR exome AF: 0.984

Gnomad4 ASJ exome AF: 0.984

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.998

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.998

Gnomad4 OTH exome AF: 0.984

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

Gnomad4 AFR AF: 0.826

Gnomad4 AMR AF: 0.974

Gnomad4 ASJ AF: 0.988

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.998

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.953

Alfa AF: 0.976 Hom.: 37391

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -

Aortic aneurysm, familial thoracic 7 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 11, 2016	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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.2
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs865358; hg19: chr3-123418913;