3-123640516-C-T

Position:

chr3-123640516-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_053025.4(MYLK):c.4620-12G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,613,558 control chromosomes in the GnomAD database, including 974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 83 hom., cov: 31)

Exomes 𝑓: 0.032 ( 891 hom. )

Consequence

MYLK
NM_053025.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001352

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.14

Variant links:

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 links:

MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

MYLK-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 3-123640516-C-T is Benign according to our data. Variant chr3-123640516-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123640516-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0293 (4466/152278) while in subpopulation NFE AF= 0.0344 (2341/68014). AF 95% confidence interval is 0.0333. There are 83 homozygotes in gnomad4. There are 2059 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 83 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK	NM_053025.4 linkuse as main transcript	c.4620-12G>A		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 linkuse as main transcript	c.4620-12G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_053025.4	ENSP00000353452	P4	Q15746-1
MYLK-AS1	ENST00000485162.5 linkuse as main transcript	n.523-3988C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0293

AC:

4462

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0343

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0285

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.0240

AC:

6016

AN:

250630

Hom.:

AF XY:

0.0241

AC XY:

3268

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.0346

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.0270

Gnomad NFE exome

AF:

0.0336

Gnomad OTH exome

AF:

0.0229

GnomAD4 exome

AF:

0.0322

AC:

47125

AN:

1461280

Hom.:

891

Cov.:

AF XY:

0.0317

AC XY:

23069

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.0356

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0124

Gnomad4 FIN exome

AF:

0.0257

Gnomad4 NFE exome

AF:

0.0367

Gnomad4 OTH exome

AF:

0.0284

GnomAD4 genome

AF:

0.0293

AC:

4466

AN:

152278

Hom.:

Cov.:

AF XY:

0.0277

AC XY:

2059

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0343

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.0285

Gnomad4 NFE

AF:

0.0344

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0310

Hom.:

Bravo

AF:

0.0291

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: MYLK c.4620-12G>A 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 0.024 in 250630 control chromosomes in the gnomAD database, including 92 homozygotes. The observed variant frequency is approximately 960-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Aortic aneurysm, familial thoracic 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.32

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over