NM_053025.4:c.5003_5017dupAAACCTTGGCCAACG

Variant names:

• chr3-123629570-A-ACGTTGGCCAAGGTTT
• rs1553774774
• NM_053025.4:c.5003_5017dupAAACCTTGGCCAACG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_053025.4(MYLK):​c.5003_5017dupAAACCTTGGCCAACG​(p.Glu1668_Asn1672dup) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V1673V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYLK NM_053025.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_053025.4.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.5003_5017dupAAACCTTGGCCAACG	p.Glu1668_Asn1672dup	conservative_inframe_insertion	Exon 30 of 34	NP_444253.3
	MYLK	NM_053026.4		c.4796_4810dupAAACCTTGGCCAACG	p.Glu1599_Asn1603dup	conservative_inframe_insertion	Exon 29 of 33	NP_444254.3
	MYLK	NM_001321309.2		c.4475_4489dupAAACCTTGGCCAACG	p.Glu1492_Asn1496dup	conservative_inframe_insertion	Exon 29 of 33	NP_001308238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.5003_5017dupAAACCTTGGCCAACG	p.Glu1668_Asn1672dup	conservative_inframe_insertion	Exon 30 of 34	ENSP00000353452.3
	MYLK	ENST00000464489.5	TSL:1	n.*4582_*4596dupAAACCTTGGCCAACG		non_coding_transcript_exon	Exon 29 of 33	ENSP00000417798.1
	MYLK-AS1	ENST00000470449.3	TSL:1	n.355_369dupGGCCAAGGTTTCGTT		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic aneurysm, familial thoracic 7 Uncertain:1

Mar 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5003_5017dup, results in the insertion of 5 amino acid(s) to the MYLK protein (p.Glu1668_Asn1672dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 539079). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553774774; hg19: chr3-123348417;