rs1553639921

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000258.3(MYL3):​c.283G>T​(p.Val95Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MYL3
NM_000258.3 missense

Scores

3
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000258.3
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYL3NM_000258.3 linkuse as main transcriptc.283G>T p.Val95Phe missense_variant 3/7 ENST00000292327.6 NP_000249.1 P08590A0A024R2Q5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYL3ENST00000292327.6 linkuse as main transcriptc.283G>T p.Val95Phe missense_variant 3/71 NM_000258.3 ENSP00000292327.4 P08590

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 27, 2017This sequence change replaces valine with phenylalanine at codon 95 of the MYL3 protein (p.Val95Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYL3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
CardioboostCm
Uncertain
0.22
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D;D
Eigen
Benign
0.15
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.68
D;D
MetaSVM
Uncertain
-0.038
T
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-4.1
D;D
REVEL
Uncertain
0.61
Sift
Benign
0.049
D;D
Sift4G
Benign
0.092
T;T
Polyphen
0.20
B;B
Vest4
0.83
MutPred
0.45
Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP
0.98
MPC
1.2
ClinPred
0.99
D
GERP RS
4.4
Varity_R
0.61
gMVP
0.87

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.

Other links and lift over

dbSNP: rs1553639921; hg19: chr3-46902190; API