rs1553639921

Variant names:

• chr3-46860700-C-A
• rs1553639921
• NM_000258.3:c.283G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000258.3(MYL3):​c.283G>T​(p.Val95Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). The gene MYL3 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16
• Publications: 0 publications found

Genes affected

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

MYL3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 8

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for MYL3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 15 pathogenic changes around while only 6 benign (71%) in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.75572 (below the threshold of 3.09). Trascript score misZ: 1.3243 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 8, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000258.3. 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
	MYL3	NM_000258.3	MANE Select	c.283G>T	p.Val95Phe	missense	Exon 3 of 7	NP_000249.1	P08590
	MYL3	NM_001406937.1		c.283G>T	p.Val95Phe	missense	Exon 3 of 6	NP_001393866.1	P08590
	MYL3	NM_001406938.1		c.283G>T	p.Val95Phe	missense	Exon 5 of 9	NP_001393867.1	P08590

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL3	ENST00000292327.6	TSL:1 MANE Select	c.283G>T	p.Val95Phe	missense	Exon 3 of 7	ENSP00000292327.4	P08590
	MYL3	ENST00000395869.5	TSL:1	c.283G>T	p.Val95Phe	missense	Exon 3 of 6	ENSP00000379210.1	P08590
	MYL3	ENST00000713934.1		c.415G>T	p.Val139Phe	missense	Exon 3 of 7	ENSP00000519231.1	A0AAQ5BH63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostCm	Uncertain	0.22
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.61
Sift	Benign	0.049	D
Sift4G	Benign	0.092	T
Polyphen		0.20	B
Vest4		0.83
MutPred		0.45		Loss of loop (P = 0.1242)
MVP		0.98
MPC		1.2
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.61
gMVP		0.87
Mutation Taster		=50/50

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: rs1553639921; hg19: chr3-46902190;