chr3-123612927-T-TTAAG

Position:

• chr3-123612927-T-TTAAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_053025.4(MYLK):​c.*1177_*1178insCTTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 142,144 control chromosomes in the GnomAD database, including 194 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (194 hom., cov: 32)
  • Exomes 𝑓: 0.019 (0 hom.)
• Consequence: MYLK NM_053025.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.17

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 3-123612927-T-TTAAG is Benign according to our data. Variant chr3-123612927-T-TTAAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 342835.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.*1177_*1178insCTTA		3_prime_UTR_variant	34/34	ENST00000360304.8
MYLK-AS1	NR_038266.2	n.290-16565_290-16562dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.*1177_*1178insCTTA		3_prime_UTR_variant	34/34	5	NM_053025.4	P4
MYLK-AS1	ENST00000485162.5	n.261-16565_261-16562dup		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3389 AN: 141622 Hom.: 190 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00867

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.0920

Gnomad FIN AF: 0.00848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0249

GnomAD4 exome AF: 0.0185 AC: 8 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.0231 AC XY: 6 AN XY: 260

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0240 AC: 3398 AN: 141712 Hom.: 194 Cov.: 32 AF XY: 0.0271 AC XY: 1878 AN XY: 69230

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.00867

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.0917

Gnomad4 FIN AF: 0.00848

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0276

Alfa AF: 0.0151 Hom.: 7

Bravo AF: 0.0236

Asia WGS AF: 0.157 AC: 528 AN: 3366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs146691098; hg19: chr3-123331774;