rs147584015

Variant names:

• chr3-46863310-A-G
• rs147584015
• NM_000258.3:c.81T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000258.3(MYL3):​c.81T>C​(p.Pro27Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,614,056 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: MYL3 NM_000258.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -1.93
• Publications: 1 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-46863310-A-G is Benign according to our data. Variant chr3-46863310-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43130.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS2: High AC in GnomAd4 at 186 AD,SD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000258.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL3	NM_000258.3	MANE Select	c.81T>C	p.Pro27Pro	synonymous	Exon 1 of 7	NP_000249.1	P08590
	MYL3	NM_001406937.1		c.81T>C	p.Pro27Pro	synonymous	Exon 1 of 6	NP_001393866.1	P08590
	MYL3	NM_001406938.1		c.81T>C	p.Pro27Pro	synonymous	Exon 3 of 9	NP_001393867.1	P08590

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL3	ENST00000292327.6	TSL:1 MANE Select	c.81T>C	p.Pro27Pro	synonymous	Exon 1 of 7	ENSP00000292327.4	P08590
	MYL3	ENST00000395869.5	TSL:1	c.81T>C	p.Pro27Pro	synonymous	Exon 1 of 6	ENSP00000379210.1	P08590
	MYL3	ENST00000713934.1		c.81T>C	p.Pro27Pro	synonymous	Exon 1 of 7	ENSP00000519231.1	A0AAQ5BH63

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.00

GnomAD2 exomes AF: 0.000371 AC: 93 AN: 250476 AF XY: 0.000266

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000192 AC: 280 AN: 1461750 Hom.: 1 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727190

African (AFR) AF: 0.00702 AC: 235 AN: 33478

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111990

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74478

African (AFR) AF: 0.00428 AC: 178 AN: 41566

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000960 Hom.: 1

Bravo AF: 0.00155

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.090
DANN	Benign	0.46
PhyloP100		-1.9
PromoterAI		0.0072	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147584015; hg19: chr3-46904800;