3-46858026-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.05

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 -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/exons	MANE	UniProt
MYL3	NM_000258.3	c.*89G>A		3_prime_UTR_variant	7/7	ENST00000292327.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL3	ENST00000292327.6	c.*89G>A		3_prime_UTR_variant	7/7	1	NM_000258.3	P1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27741 AN: 151872 Hom.: 3310 Cov.: 31

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.: 6 AF XY: 0.164 AC XY: 42339 AN XY: 258580

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.: 31 AF XY: 0.187 AC XY: 13912 AN XY: 74280

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 8 Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

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

Other links and lift over

dbSNP: rs1042973; hg19: chr3-46899516; COSMIC: COSV52767732; COSMIC: COSV52767732;