chr19-50268255-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001145809.2(MYH14):c.2921G>T(p.Arg974Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R974H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MYH14
NM_001145809.2 missense
NM_001145809.2 missense
Scores
3
5
5
Clinical Significance
Conservation
PhyloP100: 2.04
Genes affected
MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-50268255-G-T is Pathogenic according to our data. Variant chr19-50268255-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 30739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50268255-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH14 | NM_001145809.2 | c.2921G>T | p.Arg974Leu | missense_variant | 24/43 | ENST00000642316.2 | |
MYH14 | NM_001077186.2 | c.2822G>T | p.Arg941Leu | missense_variant | 23/42 | ||
MYH14 | NM_024729.4 | c.2798G>T | p.Arg933Leu | missense_variant | 22/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH14 | ENST00000642316.2 | c.2921G>T | p.Arg974Leu | missense_variant | 24/43 | NM_001145809.2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1418752Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 701990
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1418752
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
701990
Gnomad4 AFR exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | This variant has been previously reported as disease-causing and was identified in a 12 yo male with axonal neuropathy and neurosensory hearing loss. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2022 | Published functional studies suggest a damaging effect due to impairments in mitochondrial fission (Almutawa et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21480433, 31231018, 27875632, 26257172, 28708278) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T;.;T;T;T
Polyphen
P;P;B;B;.;B;B
Vest4
MutPred
0.40
.;.;Loss of MoRF binding (P = 0.0176);.;.;.;Loss of MoRF binding (P = 0.0176);
MVP
MPC
0.70
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