rs797045727
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_002470.4(MYH3):c.1504T>G(p.Tyr502Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
MYH3
NM_002470.4 missense
NM_002470.4 missense
Scores
13
1
2
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, MYH3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.971
PP5
?
Variant 17-10642903-A-C is Pathogenic according to our data. Variant chr17-10642903-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211550.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.1504T>G | p.Tyr502Asp | missense_variant | 15/41 | ENST00000583535.6 | |
MYH3 | XM_011523870.4 | c.1504T>G | p.Tyr502Asp | missense_variant | 15/41 | ||
MYH3 | XM_011523871.3 | c.1504T>G | p.Tyr502Asp | missense_variant | 15/41 | ||
MYH3 | XM_047436127.1 | c.1504T>G | p.Tyr502Asp | missense_variant | 17/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.1504T>G | p.Tyr502Asp | missense_variant | 15/41 | 5 | NM_002470.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Freeman-Sheldon syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 30, 2015 | DNA sequence analysis of the MYH3 gene demonstrated a sequence change, c.1504T>G, in exon 15 that results in an amino acid change, p.Tyr502Asp. The p.Tyr502Asp change affects a highly conserved amino acid residue located in a domain of the MYH3 protein that is known to be functional. The p.Tyr502Asp substitution appears to be deleterious/possibly damaging using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, MutationTaster). This particular amino acid change does not appear to have been described in the literature in other patients with MYH3-related disorders or as a benign sequence change in the MYH3 gene. The p.Tyr502Asp amino acid change occurs in a region of the MYH3 gene where other missense sequence changes have been described in patients with MYH3-related distal. arthrogryposis. To date, the vast majority of pathogenic variants described in the MYH3 gene have been missense. In addition, this variant was found to be present in the de novo state in the patient tested in our laboratory. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0391);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at