rs139544273
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6BP7BS2_Supporting
The NM_002470.4(MYH3):āc.3072C>Gā(p.Thr1024Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,614,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00049 ( 0 hom., cov: 32)
Exomes š: 0.00074 ( 1 hom. )
Consequence
MYH3
NM_002470.4 synonymous
NM_002470.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.779
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 Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
Variant 17-10639328-G-C is Benign according to our data. Variant chr17-10639328-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258678.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
BP7
Synonymous conserved (PhyloP=0.779 with no splicing effect.
BS2
High AC in GnomAd4 at 75 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.3072C>G | p.Thr1024Thr | synonymous_variant | 24/41 | ENST00000583535.6 | NP_002461.2 | |
MYH3 | XM_011523870.4 | c.3072C>G | p.Thr1024Thr | synonymous_variant | 24/41 | XP_011522172.1 | ||
MYH3 | XM_011523871.3 | c.3072C>G | p.Thr1024Thr | synonymous_variant | 24/41 | XP_011522173.1 | ||
MYH3 | XM_047436127.1 | c.3072C>G | p.Thr1024Thr | synonymous_variant | 26/43 | XP_047292083.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.3072C>G | p.Thr1024Thr | synonymous_variant | 24/41 | 5 | NM_002470.4 | ENSP00000464317.1 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000406 AC: 102AN: 251438Hom.: 0 AF XY: 0.000405 AC XY: 55AN XY: 135912
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GnomAD4 exome AF: 0.000745 AC: 1089AN: 1461882Hom.: 1 Cov.: 66 AF XY: 0.000704 AC XY: 512AN XY: 727244
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GnomAD4 genome AF: 0.000493 AC: 75AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74396
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Distal arthrogryposis type 2B1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Freeman-Sheldon syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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