rs150007422

Variant names:

• chr3-123701439-G-A
• rs150007422
• NM_053025.4:c.2461C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123701439-G-A
• chr3-123701439-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_053025.4(MYLK):​c.2461C>T​(p.Arg821Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 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. R821Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MYLK NM_053025.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003451
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 0.614
• Publications: 4 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)

LOC105369194 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17499173).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000214 (313/1461802) while in subpopulation NFE AF = 0.000273 (304/1111988). AF 95% confidence interval is 0.000248. There are 0 homozygotes in GnomAdExome4. There are 156 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2461C>T	p.Arg821Trp	missense splice_region	Exon 17 of 34	NP_444253.3
	MYLK	NM_053027.4		c.2461C>T	p.Arg821Trp	missense splice_region	Exon 17 of 33	NP_444255.3
	MYLK	NM_053026.4		c.2254C>T	p.Arg752Trp	missense splice_region	Exon 16 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.2461C>T	p.Arg821Trp	missense splice_region	Exon 17 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000504946.6	TSL:1	c.70C>T	p.Arg24Trp	missense splice_region	Exon 1 of 4	ENSP00000510315.1	A0A8I5KYZ0
	MYLK	ENST00000464489.5	TSL:1	n.*2040C>T		splice_region non_coding_transcript_exon	Exon 16 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251454 AF XY: 0.000169

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000214 AC: 313 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 156 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000273 AC: 304 AN: 1111988

Other (OTH) AF: 0.0000662 AC: 4 AN: 60384

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74308

African (AFR) AF: 0.000145 AC: 6 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68004

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	2	-	Aortic aneurysm, familial thoracic 7 (2)
-	1	-	Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.097	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.61
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.23
MVP		0.73
MPC		0.43
ClinPred		0.13	T
GERP RS		-0.35
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.10		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: rs150007422; hg19: chr3-123420286; COSMIC: COSV104664210; COSMIC: COSV104664210;