chr3-123725938-A-T

Position:

• chr3-123725938-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.1651+6T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,613,104 control chromosomes in the GnomAD database, including 38,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2636 hom., cov: 33)
  • Exomes 𝑓: 0.21 (36116 hom.)
• Consequence: MYLK NM_053025.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.3909
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.152

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-123725938-A-T is Benign according to our data. Variant chr3-123725938-A-T is described in ClinVar as [Benign]. Clinvar id is 226756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123725938-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.1651+6T>A		splice_donor_region_variant, intron_variant		ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.1651+6T>A		splice_donor_region_variant, intron_variant		5	NM_053025.4	P4

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25194 AN: 152112 Hom.: 2637 Cov.: 33

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.00580

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.164 AC: 41102 AN: 249904 Hom.: 4324 AF XY: 0.167 AC XY: 22588 AN XY: 135008

Gnomad AFR exome AF: 0.0608

Gnomad AMR exome AF: 0.0968

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.00419

Gnomad SAS exome AF: 0.0771

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.212 AC: 309780 AN: 1460874 Hom.: 36116 Cov.: 33 AF XY: 0.209 AC XY: 151628 AN XY: 726606

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.00375

Gnomad4 SAS exome AF: 0.0779

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.166 AC: 25200 AN: 152230 Hom.: 2636 Cov.: 33 AF XY: 0.161 AC XY: 11995 AN XY: 74430

Gnomad4 AFR AF: 0.0630

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.00600

Gnomad4 SAS AF: 0.0728

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.191

Alfa AF: 0.186 Hom.: 986

Bravo AF: 0.156

Asia WGS AF: 0.0500 AC: 176 AN: 3478

EpiCase AF: 0.225

EpiControl AF: 0.226

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	1651+6T>A in intron 12 of MYLK: This variant is not expected to have clinical si gnificance because it has been identified in 23.1% (1984/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs820329). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 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. -

Aortic aneurysm, familial thoracic 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.39
dbscSNV1_RF	Benign	0.52
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: rs820329; hg19: chr3-123444785;