rs727504566
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_005379.4(MYO1A):c.1055G>A(p.Arg352His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,034 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
MYO1A
NM_005379.4 missense
NM_005379.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
MYO1A (HGNC:7595): (myosin IA) This gene encodes a member of the myosin superfamily. The protein represents an unconventional myosin; it should not be confused with the conventional skeletal muscle myosin-1 (MYH1). Unconventional myosins contain the basic domains characteristic of conventional myosins and are further distinguished from class members by their tail domains. They function as actin-based molecular motors. Mutations in this gene have been associated with autosomal dominant deafness. Alternatively spliced variants have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.894
BS2
?
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO1A | NM_005379.4 | c.1055G>A | p.Arg352His | missense_variant | 12/28 | ENST00000300119.8 | |
MYO1A | NM_001256041.2 | c.1055G>A | p.Arg352His | missense_variant | 13/29 | ||
MYO1A | XM_047428876.1 | c.1055G>A | p.Arg352His | missense_variant | 13/29 | ||
MYO1A | XM_011538373.3 | c.1055G>A | p.Arg352His | missense_variant | 12/25 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO1A | ENST00000300119.8 | c.1055G>A | p.Arg352His | missense_variant | 12/28 | 1 | NM_005379.4 | P1 | |
MYO1A | ENST00000442789.6 | c.1055G>A | p.Arg352His | missense_variant | 13/29 | 1 | P1 | ||
MYO1A | ENST00000492945.5 | c.143G>A | p.Arg48His | missense_variant | 4/5 | 4 | |||
MYO1A | ENST00000554234.5 | c.569G>A | p.Arg190His | missense_variant, NMD_transcript_variant | 8/24 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152144Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251326Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135810
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000715 AC XY: 52AN XY: 727248
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 05, 2013 | The Arg352His variant in MYO1A has not been reported in individuals with hearing loss or in large population studies. The arginine (Arg) residue at position 352 is highly conserved across species and lies in the myosin head motor domain. In addition, computational analyses ( AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Arg352His variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0094);Loss of MoRF binding (P = 0.0094);.;
MVP
MPC
0.48
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