3-46860702-C-T

Variant names:

• chr3-46860702-C-T
• rs199474703
• NM_000258.3:c.281G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 11P and 4B. PM1 PP2 PP5_Very_Strong BS2

The NM_000258.3(MYL3):​c.281G>A​(p.Arg94His) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 4.86
• Publications: 6 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 7 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
• 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.
• PP5: Variant 3-46860702-C-T is Pathogenic according to our data. Variant chr3-46860702-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 7 AD,SD gene.

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.281G>A	p.Arg94His	missense	Exon 3 of 7	NP_000249.1	P08590
	MYL3	NM_001406937.1		c.281G>A	p.Arg94His	missense	Exon 3 of 6	NP_001393866.1	P08590
	MYL3	NM_001406938.1		c.281G>A	p.Arg94His	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.281G>A	p.Arg94His	missense	Exon 3 of 7	ENSP00000292327.4	P08590
	MYL3	ENST00000395869.5	TSL:1	c.281G>A	p.Arg94His	missense	Exon 3 of 6	ENSP00000379210.1	P08590
	MYL3	ENST00000713934.1		c.413G>A	p.Arg138His	missense	Exon 3 of 7	ENSP00000519231.1	A0AAQ5BH63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251298 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hypertrophic cardiomyopathy (3)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 8 (1)
1	-	-	not provided (2)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.040
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.94	L
PhyloP100		4.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.031	D
Polyphen		0.065	B
Vest4		0.71
MutPred		0.53		Gain of methylation at K98 (P = 0.0588)
MVP		0.93
MPC		0.43
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.20
gMVP		0.23
Mutation Taster		=18/82	disease causing (ClinVar)

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: rs199474703; hg19: chr3-46902192;