rs1441072867
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_002471.4(MYH6):c.5575G>A(p.Asp1859Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 103,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000019 ( 0 hom., cov: 22)
Exomes 𝑓: 0.000019 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MYH6
NM_002471.4 missense
NM_002471.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 7.88
Genes affected
MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, MYH6
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.924
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5575G>A | p.Asp1859Asn | missense_variant | 37/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.5575G>A | p.Asp1859Asn | missense_variant | 37/39 | 5 | NM_002471.4 | P1 | |
MYH6 | ENST00000651452.1 | n.802G>A | non_coding_transcript_exon_variant | 1/3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000194 AC: 2AN: 103156Hom.: 0 Cov.: 22
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GnomAD3 exomes AF: 0.00000429 AC: 1AN: 233300Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126894
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000194 AC: 11AN: 566824Hom.: 0 Cov.: 30 AF XY: 0.0000171 AC XY: 5AN XY: 292630
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GnomAD4 genome ? AF: 0.0000194 AC: 2AN: 103156Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 46512
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1859 of the MYH6 protein (p.Asp1859Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 470550). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH6 protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 25, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2023 | The p.D1859N variant (also known as c.5575G>A), located in coding exon 35 of the MYH6 gene, results from a G to A substitution at nucleotide position 5575. The aspartic acid at codon 1859 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at