chr3-123640522-C-T

Variant names:

• chr3-123640522-C-T
• rs41305835
• NM_053025.4:c.4620-18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_053025.4(MYLK):​c.4620-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,613,262 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (18 hom.)
• Consequence: MYLK NM_053025.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.484
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-123640522-C-T is Benign according to our data. Variant chr3-123640522-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00213 (325/152262) while in subpopulation SAS AF = 0.00538 (26/4832). AF 95% confidence interval is 0.00377. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AD,AR gene

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.4620-18G>A		intron	N/A	NP_444253.3
	MYLK	NM_053027.4		c.4620-18G>A		intron	N/A	NP_444255.3
	MYLK	NM_053026.4		c.4413-18G>A		intron	N/A	NP_444254.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.4620-18G>A		intron	N/A	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*4199-18G>A		intron	N/A	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000687848.1		c.4650-18G>A		intron	N/A	ENSP00000508761.1	A0A8I5KU53

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00272 AC: 680 AN: 250268 AF XY: 0.00310

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00319 AC: 4655 AN: 1461000 Hom.: 18 Cov.: 32 AF XY: 0.00331 AC XY: 2404 AN XY: 726844

African (AFR) AF: 0.000359 AC: 12 AN: 33452

American (AMR) AF: 0.00201 AC: 90 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00608 AC: 524 AN: 86228

European-Finnish (FIN) AF: 0.000581 AC: 31 AN: 53394

Middle Eastern (MID) AF: 0.00252 AC: 13 AN: 5150

European-Non Finnish (NFE) AF: 0.00342 AC: 3800 AN: 1111894

Other (OTH) AF: 0.00250 AC: 151 AN: 60328

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74446

African (AFR) AF: 0.000577 AC: 24 AN: 41562

American (AMR) AF: 0.00163 AC: 25 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4832

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00343 AC: 233 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00225

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Aortic aneurysm, familial thoracic 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.71
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

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: rs41305835; hg19: chr3-123359369;