rs199639940
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6
The NM_000258.3(MYL3):c.92G>A(p.Arg31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000258.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYL3 | NM_000258.3 | c.92G>A | p.Arg31His | missense_variant | Exon 1 of 7 | ENST00000292327.6 | NP_000249.1 | |
MYL3 | NM_001406937.1 | c.92G>A | p.Arg31His | missense_variant | Exon 1 of 6 | NP_001393866.1 | ||
MYL3 | NM_001406938.1 | c.92G>A | p.Arg31His | missense_variant | Exon 3 of 9 | NP_001393867.1 | ||
MYL3 | NM_001406939.1 | c.92G>A | p.Arg31His | missense_variant | Exon 3 of 9 | NP_001393868.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000839 AC: 21AN: 250332Hom.: 0 AF XY: 0.0000886 AC XY: 12AN XY: 135412
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461760Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727188
GnomAD4 genome AF: 0.0000459 AC: 7AN: 152340Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74504
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 19, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg31His vari ant in MYL3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.15% (13/8764) of East Asian chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1996399 40) and 1/427 healthy controls from one study (Kapplinger 2014). Arginine (Arg) at position 31 is not conserved in mammals or in evolutionarily distant species and 1 mammal species (manatee) carries a histidine (His) at this position, raisi ng the possibility that this change may be tolerated. In summary, while the clin ical significance of the p.Arg31His variant is uncertain, its presence in genera l population and lack of evolutionarily conservation suggest that it is more lik ely to be benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2024 | Variant summary: MYL3 c.92G>A (p.Arg31His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 281736 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 44-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYL3 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05). c.92G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Pua_2020), however, no convincing evidence for causality was provided. These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 228936). Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 13, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 27, 2020 | - - |
Hypertrophic cardiomyopathy 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 26, 2024 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2025 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Amyloidosis, hereditary systemic 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | May 20, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at