rs199639940

Variant names:

• chr3-46863299-C-A
• rs199639940
• NM_000258.3:c.92G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-46863299-C-A
• chr3-46863299-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000258.3(MYL3):​c.92G>T​(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYL3 NM_000258.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.00

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 38 pathogenic changes around while only 5 benign (88%) in NM_000258.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.75572 (below the threshold of 3.09). Trascript score misZ: 1.3243 (below the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy 8.
• BP4: Computational evidence support a benign effect (MetaRNN=0.076487094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL3	NM_000258.3	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 7	ENST00000292327.6	NP_000249.1
MYL3	NM_001406937.1	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 6		NP_001393866.1
MYL3	NM_001406938.1	c.92G>T	p.Arg31Leu	missense_variant	Exon 3 of 9		NP_001393867.1
MYL3	NM_001406939.1	c.92G>T	p.Arg31Leu	missense_variant	Exon 3 of 9		NP_001393868.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 7	1	NM_000258.3	ENSP00000292327.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53300

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1112004

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostCm	Benign	0.0038
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.5
DANN	Benign	0.85
DEOGEN2	Benign	0.33	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.55	.;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L;L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.34	N;N;D
REVEL	Benign	0.19
Sift	Benign	0.090	T;T;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.13
MutPred		0.25		Loss of glycosylation at P26 (P = 0.0018);Loss of glycosylation at P26 (P = 0.0018);Loss of glycosylation at P26 (P = 0.0018);
MVP		0.46
MPC		0.42
ClinPred		0.092	T
GERP RS		-5.7
Varity_R		0.061
gMVP		0.39
Mutation Taster		=93/7	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

Publications

LitVar

Other links and lift over

dbSNP: rs199639940; hg19: chr3-46904789;