rs192329378

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000258.3(MYL3):c.130-14G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,613,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 4 hom. )

Consequence

MYL3
NM_000258.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.269

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 3-46861001-C-A is Benign according to our data. Variant chr3-46861001-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 43119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46861001-C-A is described in Lovd as [Benign]. Variant chr3-46861001-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00194 (296/152228) while in subpopulation AMR AF= 0.00484 (74/15296). AF 95% confidence interval is 0.00395. There are 0 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL3	NM_000258.3 linkuse as main transcript	c.130-14G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000292327.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6 linkuse as main transcript	c.130-14G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000258.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00271

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00161

AC:

404

AN:

250952

Hom.:

AF XY:

0.00172

AC XY:

234

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.000432

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00252

AC:

3686

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1812

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00292

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152228

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00484

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000898

Hom.:

Bravo

AF:

0.00199

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 8

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 13, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2012	130-14G>T in intron 01 of MYL3: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (31/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS/). 130-14G>T in intron 01 of MYL3 (allele frequenc y = 0.4%, 31/7020) ** -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.9

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over