chr3-38138670-CGACCGCGCTGAGGCTCCAG-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BS1_Supporting
The NM_002468.5(MYD88):c.-24_-6del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,561,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00058 ( 0 hom. )
Consequence
MYD88
NM_002468.5 5_prime_UTR
NM_002468.5 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.231
Genes affected
MYD88 (HGNC:7562): (MYD88 innate immune signal transduction adaptor) This gene encodes a cytosolic adapter protein that plays a central role in the innate and adaptive immune response. This protein functions as an essential signal transducer in the interleukin-1 and Toll-like receptor signaling pathways. These pathways regulate that activation of numerous proinflammatory genes. The encoded protein consists of an N-terminal death domain and a C-terminal Toll-interleukin1 receptor domain. Patients with defects in this gene have an increased susceptibility to pyogenic bacterial infections. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-38138670-CGACCGCGCTGAGGCTCCAG-C is Pathogenic according to our data. Variant chr3-38138670-CGACCGCGCTGAGGCTCCAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469578.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000578 (814/1409132) while in subpopulation NFE AF= 0.000711 (771/1083860). AF 95% confidence interval is 0.00067. There are 0 homozygotes in gnomad4_exome. There are 375 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYD88 | NM_002468.5 | c.-24_-6del | 5_prime_UTR_variant | 1/5 | ENST00000650905.2 | NP_002459.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYD88 | ENST00000650905.2 | c.-24_-6del | 5_prime_UTR_variant | 1/5 | NM_002468.5 | ENSP00000498360 | A1 |
Frequencies
GnomAD3 genomes 0.000296 AC: 45AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000364 AC: 75AN: 206006Hom.: 0 AF XY: 0.000360 AC XY: 41AN XY: 113806
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GnomAD4 exome AF: 0.000578 AC: 814AN: 1409132Hom.: 0 AF XY: 0.000540 AC XY: 375AN XY: 694786
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GnomAD4 genome 0.000296 AC: 45AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74374
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pyogenic bacterial infections due to MyD88 deficiency Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 29, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Ala6Profs*39) in the MYD88 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYD88 are known to be pathogenic (PMID: 18669862, 20538326). This variant is present in population databases (rs746651350, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with MYD88-related conditions. ClinVar contains an entry for this variant (Variation ID: 469578). For these reasons, this variant has been classified as Pathogenic. - |
MYD88-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | The MYD88 c.16_34del19 variant is predicted to result in a frameshift and premature protein termination (p.Ala6Profs*39). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be causative of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at