rs387907272
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002468.5(MYD88):c.755T>C(p.Leu252Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
MYD88
NM_002468.5 missense
NM_002468.5 missense
Scores
2
8
4
Clinical Significance
Conservation
PhyloP100: 7.87
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;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYD88 | NM_002468.5 | c.755T>C | p.Leu252Pro | missense_variant | 5/5 | ENST00000650905.2 | NP_002459.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYD88 | ENST00000650905.2 | c.755T>C | p.Leu252Pro | missense_variant | 5/5 | NM_002468.5 | ENSP00000498360 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251436Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135882
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461750Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727134
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:6Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Macroglobulinemia, Waldenstrom, somatic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 06, 2012 | - - |
B-cell chronic lymphocytic leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Multiple myeloma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant lymphoma, large B-cell, diffuse Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Wasik Lab, Fox Chase Cancer Center | Jul 25, 2023 | This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. MYD88 L265P was detected in the tumor at presentation and with increased variant allele frequency, genomic copy number, and RNA expression at recurrence. MYD88 is an essential signaling adaptor protein that interacts with Toll-like receptors (TLR), kinases IRAK1 and IRAK4 to form a ‘myddosome complex’. The L265P mutation is a gain of function oncogenic mutation resulting in spontaneous assembly of the myddosome complex (Ngo et al. 2011) and ultimately NF-kB pathway activation. - |
Lymphoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Dec 26, 2014 | - - |
Non-Hodgkin lymphoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Pyogenic bacterial infections due to MyD88 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 03, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects MYD88 function (PMID: 21179087). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 37055). This variant has been reported as a recurrent somatic mutation in individuals affected with Waldenström’s macroglobulinemia and other related lymphoid neoplasms (PMID: 22931316, 21179087, 23355535), but has not been reported as a germline variant. This variant is present in population databases (rs387907272, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 265 of the MYD88 protein (p.Leu265Pro). - |
Neoplasm Other:1
-, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;N;N
PrimateAI
Uncertain
T
REVEL
Pathogenic
Polyphen
1.0
.;D;D;.;.
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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