chr3-123831616-G-A

Variant names:

• chr3-123831616-G-A
• rs2700352
• NM_053025.4:c.-72C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.-72C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 290,724 control chromosomes in the GnomAD database, including 5,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2249 hom., cov: 32)
  • Exomes 𝑓: 0.19 (2855 hom.)
• Consequence: MYLK NM_053025.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 18 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 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-123831616-G-A is Benign according to our data. Variant chr3-123831616-G-A is described in ClinVar as Benign. ClinVar VariationId is 342911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK	NM_053025.4	c.-72C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 34	ENST00000360304.8	NP_444253.3
MYLK	NM_053025.4	c.-72C>T		5_prime_UTR_variant	Exon 3 of 34	ENST00000360304.8	NP_444253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK	ENST00000360304.8	c.-72C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 34	5	NM_053025.4	ENSP00000353452.3
MYLK	ENST00000360304.8	c.-72C>T		5_prime_UTR_variant	Exon 3 of 34	5	NM_053025.4	ENSP00000353452.3

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25096 AN: 152020 Hom.: 2246 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.190 AC: 26287 AN: 138586 Hom.: 2855 Cov.: 3 AF XY: 0.195 AC XY: 14523 AN XY: 74586

African (AFR) AF: 0.106 AC: 401 AN: 3778

American (AMR) AF: 0.124 AC: 876 AN: 7038

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 518 AN: 2774

East Asian (EAS) AF: 0.0419 AC: 186 AN: 4442

South Asian (SAS) AF: 0.241 AC: 5547 AN: 22972

European-Finnish (FIN) AF: 0.214 AC: 1177 AN: 5506

Middle Eastern (MID) AF: 0.184 AC: 81 AN: 440

European-Non Finnish (NFE) AF: 0.190 AC: 16258 AN: 85388

Other (OTH) AF: 0.199 AC: 1243 AN: 6248

GnomAD4 genome AF: 0.165 AC: 25118 AN: 152138 Hom.: 2249 Cov.: 32 AF XY: 0.165 AC XY: 12298 AN XY: 74356

African (AFR) AF: 0.114 AC: 4747 AN: 41512

American (AMR) AF: 0.125 AC: 1917 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 678 AN: 3470

East Asian (EAS) AF: 0.0453 AC: 234 AN: 5162

South Asian (SAS) AF: 0.225 AC: 1082 AN: 4814

European-Finnish (FIN) AF: 0.217 AC: 2289 AN: 10566

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13595 AN: 68004

Other (OTH) AF: 0.172 AC: 363 AN: 2112

Alfa AF: 0.184 Hom.: 3606

Bravo AF: 0.153

Asia WGS AF: 0.156 AC: 543 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aortic aneurysm, familial thoracic 7 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		-1.3
PromoterAI		-0.032	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2700352; hg19: chr3-123550463;