rs45477891

Variant names:

• chr3-123722130-T-C
• rs45477891
• NM_053025.4:c.1802A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-123722130-T-C
• chr3-123722130-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_053025.4(MYLK):​c.1802A>G​(p.His601Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,565,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H601P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: MYLK NM_053025.4 missense, splice_region
• Scores: Splicing: ADA: 0.0006896
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.750
• Publications: 3 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
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.091726035).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.1802A>G	p.His601Arg	missense splice_region	Exon 13 of 34	NP_444253.3
	MYLK	NM_053027.4		c.1802A>G	p.His601Arg	missense splice_region	Exon 13 of 33	NP_444255.3
	MYLK	NM_053026.4		c.1595A>G	p.His532Arg	missense splice_region	Exon 12 of 33	NP_444254.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.1802A>G	p.His601Arg	missense splice_region	Exon 13 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*1381A>G		splice_region non_coding_transcript_exon	Exon 12 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000464489.5	TSL:1	n.*1381A>G		3_prime_UTR	Exon 12 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000115 AC: 2 AN: 173830 AF XY: 0.0000108

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000141

Gnomad OTH exome AF: 0.000214

GnomAD4 exome AF: 0.00000920 AC: 13 AN: 1413020 Hom.: 0 Cov.: 42 AF XY: 0.00000573 AC XY: 4 AN XY: 698348

African (AFR) AF: 0.00 AC: 0 AN: 32258

American (AMR) AF: 0.00 AC: 0 AN: 37872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25280

East Asian (EAS) AF: 0.000108 AC: 4 AN: 36906

South Asian (SAS) AF: 0.00 AC: 0 AN: 79970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49576

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5718

European-Non Finnish (NFE) AF: 0.00000644 AC: 7 AN: 1086858

Other (OTH) AF: 0.00 AC: 0 AN: 58582

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152252 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Aortic aneurysm, familial thoracic 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.0
DANN	Benign	0.19
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N
PhyloP100		0.75
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.078
Sift	Benign	0.31	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.46
MPC		0.19
ClinPred		0.035	T
GERP RS		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.40
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00069
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.13		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: rs45477891; hg19: chr3-123440977;