Genetic Variant NM_000258.3:c.*89G>A (chr3-46858026-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000258.3(MYL3):c.*89G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 640,720 control chromosomes in the GnomAD database, including 11,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3313 hom., cov: 31)

Exomes 𝑓: 0.15 ( 7714 hom. )

Consequence

MYL3
NM_000258.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.05

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=-0.81).

BP6

Variant 3-46858026-C-T is Benign according to our data. Variant chr3-46858026-C-T is described in ClinVar as [Benign]. Clinvar id is 345568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46858026-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3 link	c.*89G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000292327.6	NP_000249.1	P08590A0A024R2Q5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327 link	c.*89G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_000258.3	ENSP00000292327.4		P08590

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27741

AN:

151872

Hom.:

3310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.375

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.176

GnomAD4 exome

AF:

0.152

AC:

74412

AN:

488730

Hom.:

7714

Cov.:

AF XY:

0.164

AC XY:

42339

AN XY:

258580

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.106

Gnomad4 ASJ exome

AF:

0.185

Gnomad4 EAS exome

AF:

0.221

Gnomad4 SAS exome

AF:

0.370

Gnomad4 FIN exome

AF:

0.126

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.158

GnomAD4 genome

AF:

0.183

AC:

27780

AN:

151990

Hom.:

3313

Cov.:

AF XY:

0.187

AC XY:

13912

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.316

Gnomad4 AMR

AF:

0.121

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.224

Gnomad4 SAS

AF:

0.375

Gnomad4 FIN

AF:

0.133

Gnomad4 NFE

AF:

0.106

Gnomad4 OTH

AF:

0.176

Alfa

AF:

0.124

Hom.:

2036

Bravo

AF:

0.182

Asia WGS

AF:

0.279

AC:

969

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy 8

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.4

DANN

Benign

0.73

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

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