chr17-10642832-G-A
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_002470.4(MYH3):c.1575C>T(p.Ile525Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,614,062 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0048 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00052 ( 7 hom. )
Consequence
MYH3
NM_002470.4 synonymous
NM_002470.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.924
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 -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
Variant 17-10642832-G-A is Benign according to our data. Variant chr17-10642832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.924 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00484 (737/152234) while in subpopulation AFR AF= 0.0171 (709/41548). AF 95% confidence interval is 0.016. There are 4 homozygotes in gnomad4. There are 347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 737 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.1575C>T | p.Ile525Ile | synonymous_variant | 15/41 | ENST00000583535.6 | NP_002461.2 | |
MYH3 | XM_011523870.4 | c.1575C>T | p.Ile525Ile | synonymous_variant | 15/41 | XP_011522172.1 | ||
MYH3 | XM_011523871.3 | c.1575C>T | p.Ile525Ile | synonymous_variant | 15/41 | XP_011522173.1 | ||
MYH3 | XM_047436127.1 | c.1575C>T | p.Ile525Ile | synonymous_variant | 17/43 | XP_047292083.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.1575C>T | p.Ile525Ile | synonymous_variant | 15/41 | 5 | NM_002470.4 | ENSP00000464317.1 |
Frequencies
GnomAD3 genomes AF: 0.00484 AC: 737AN: 152116Hom.: 4 Cov.: 32
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GnomAD3 exomes AF: 0.00118 AC: 298AN: 251494Hom.: 3 AF XY: 0.000839 AC XY: 114AN XY: 135922
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GnomAD4 exome AF: 0.000525 AC: 767AN: 1461828Hom.: 7 Cov.: 35 AF XY: 0.000437 AC XY: 318AN XY: 727210
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GnomAD4 genome AF: 0.00484 AC: 737AN: 152234Hom.: 4 Cov.: 32 AF XY: 0.00466 AC XY: 347AN XY: 74432
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2021 | - - |
not specified Benign:1
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 13, 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. - |
Freeman-Sheldon syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;C5193098:Arthrogryposis, distal, type 2B3;C5193114:Contractures, pterygia, and variable skeletal fusions syndrome 1B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 15, 2022 | - - |
Distal arthrogryposis type 2B1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
Computational scores
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Name
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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