NM_000258.3:c.382G>T

Variant names:

• chr3-46859574-C-A
• rs199474704
• NM_000258.3:c.382G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000258.3(MYL3):​c.382G>T​(p.Gly128Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.91
• Publications: 3 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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a domain EF-hand 2 (size 35) in uniprot entity MYL3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-46859573-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 222736.
• 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, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy 8.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

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.382G>T	p.Gly128Cys	missense	Exon 4 of 7	NP_000249.1	P08590
	MYL3	NM_001406937.1		c.382G>T	p.Gly128Cys	missense	Exon 4 of 6	NP_001393866.1	P08590
	MYL3	NM_001406938.1		c.382G>T	p.Gly128Cys	missense	Exon 6 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.382G>T	p.Gly128Cys	missense	Exon 4 of 7	ENSP00000292327.4	P08590
	MYL3	ENST00000395869.5	TSL:1	c.382G>T	p.Gly128Cys	missense	Exon 4 of 6	ENSP00000379210.1	P08590
	MYL3	ENST00000713934.1		c.514G>T	p.Gly172Cys	missense	Exon 4 of 7	ENSP00000519231.1	A0AAQ5BH63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.51		Gain of glycosylation at T129 (P = 0.0184)
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.70
gMVP		0.82
Mutation Taster		=6/94	disease causing

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: rs199474704; hg19: chr3-46901064;