rs199474709

Variant names:

• chr3-46858378-G-A
• rs199474709
• NM_000258.3:c.559+6C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000258.3(MYL3):​c.559+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: MYL3 NM_000258.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002937
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.282
• Publications: 2 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: PanelApp Australia, 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-46858378-G-A is Benign according to our data. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858378-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 31781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 110 AD,SD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.559+6C>T		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.559+6C>T		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251324 AF XY: 0.000147

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 727226

African (AFR) AF: 0.00230 AC: 77 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

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: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112006

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000739 AC XY: 55 AN XY: 74464

African (AFR) AF: 0.00250 AC: 104 AN: 41550

American (AMR) AF: 0.000327 AC: 5 AN: 15300

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: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000547 Hom.: 0

Bravo AF: 0.000774

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 16, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 559+6C>T variant (MYL3) has been reported in one individual with HCM (Morita 2008) but was also detected in 0.18% (7/3738) of African American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS/; dbSNP rs199474709). This frequency suggests that the variant is more likely benign although a modifying role cannot be excluded. -

Hypertrophic cardiomyopathy Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Nov 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Other:1

Mar 18, 2012

Leiden Muscular Dystrophy (MYL3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.3
DANN	Benign	0.60
PhyloP100		0.28
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.036
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: rs199474709; hg19: chr3-46899868;