rs2233264

chr3-46863322-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000258.3(MYL3):c.69C>T(p.Pro23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,958 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (65 hom., cov: 32)
  • Exomes 𝑓: 0.011 (322 hom.)
• Consequence: MYL3 NM_000258.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -6.13

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-46863322-G-A is Benign according to our data. Variant chr3-46863322-G-A is described in ClinVar as [Benign]. Clinvar id is 43129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46863322-G-A is described in Lovd as [Benign]. Variant chr3-46863322-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL3	NM_000258.3	c.69C>T	p.Pro23=	synonymous_variant	1/7	ENST00000292327.6
MYL3	NM_001406937.1	c.69C>T	p.Pro23=	synonymous_variant	1/6
MYL3	NM_001406938.1	c.69C>T	p.Pro23=	synonymous_variant	3/9
MYL3	NM_001406939.1	c.69C>T	p.Pro23=	synonymous_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6	c.69C>T	p.Pro23=	synonymous_variant	1/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3151 AN: 152180 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00641

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0203 AC: 5093 AN: 250612 Hom.: 150 AF XY: 0.0182 AC XY: 2469 AN XY: 135544

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.0936

Gnomad SAS exome AF: 0.00862

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.00638

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0106 AC: 15425 AN: 1461660 Hom.: 322 Cov.: 32 AF XY: 0.0102 AC XY: 7387 AN XY: 727150

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.0832

Gnomad4 SAS exome AF: 0.00860

Gnomad4 FIN exome AF: 0.0335

Gnomad4 NFE exome AF: 0.00545

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0207 AC: 3149 AN: 152298 Hom.: 65 Cov.: 32 AF XY: 0.0218 AC XY: 1623 AN XY: 74472

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.0889

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0375

Gnomad4 NFE AF: 0.00641

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00891 Hom.: 15

Bravo AF: 0.0201

Asia WGS AF: 0.0450 AC: 155 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00605

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy Benign:3

Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hypertrophic cardiomyopathy 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs2233264; hg19: chr3-46904812; COSMIC: COSV52767631;