3-123638190-A-T

Position:

• chr3-123638190-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_053025.4(MYLK):​c.4842T>A​(p.Asn1614Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N1614N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0920

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYLK. . Gene score misZ 1.1317 (greater than the threshold 3.09). Trascript score misZ 3.1503 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, megacystis-microcolon-intestinal hypoperistalsis syndrome, aortic aneurysm, familial thoracic 7.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.4842T>A	p.Asn1614Lys	missense_variant	29/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.4842T>A	p.Asn1614Lys	missense_variant	29/34	5	NM_053025.4	P4
MYLK-AS1	ENST00000485162.5	n.523-6314A>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250898 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461332 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Jan 17, 2022

This missense variant results in an amino acid substitution of asparagine with lysine at codon 1614 of the MYLK gene (NM_053025.3). The variant has no entry in ClinVar and has occurred in GnomAD with a total MAF of 0.0004%. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it possibly damaging, and SIFT deleterious, but no functional studies were performed to confirm these predictions. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance. -

Aortic aneurysm, familial thoracic 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1614 of the MYLK protein (p.Asn1614Lys). This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYLK protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;.;.;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	.;T;D;T;.;.
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.63	N;.;N;N;.;N
MutationTaster	Benign	0.34	P;P;P;P;P;P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N;.;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.060	T;.;T;T;T;T
Sift4G	Uncertain	0.053	T;T;T;T;T;T
Polyphen		0.98	D;D;D;P;D;P
Vest4		0.29
MutPred		0.48		Gain of ubiquitination at N1614 (P = 0.0276);.;Gain of ubiquitination at N1614 (P = 0.0276);Gain of ubiquitination at N1614 (P = 0.0276);.;Gain of ubiquitination at N1614 (P = 0.0276);
MVP		0.66
MPC		1.0
ClinPred		0.27	T
GERP RS		-0.076
Varity_R		0.056
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs820463; hg19: chr3-123357037;