11-1257702-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_002458.3(MUC5B):c.16442C>T(p.Thr5481Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,554,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 1 hom. )
Consequence
MUC5B
NM_002458.3 missense
NM_002458.3 missense
Scores
1
2
15
Clinical Significance
Conservation
PhyloP100: -0.988
Genes affected
MUC5B (HGNC:7516): (mucin 5B, oligomeric mucus/gel-forming) This gene encodes a member of the mucin family of proteins, which are highly glycosylated macromolecular components of mucus secretions. This family member is the major gel-forming mucin in mucus. It is a major contributor to the lubricating and viscoelastic properties of whole saliva, normal lung mucus and cervical mucus. This gene has been found to be up-regulated in some human diseases, including sinus mucosa of chronic rhinosinusitis (CRS), CRS with nasal polyposis, chronic obstructive pulmonary disease (COPD) and H. pylori-associated gastric disease, and it may be involved in the pathogenesis of these diseases. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.051695317).
BS2
?
High AC in GnomAd at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUC5B | NM_002458.3 | c.16442C>T | p.Thr5481Met | missense_variant | 41/49 | ENST00000529681.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUC5B | ENST00000529681.5 | c.16442C>T | p.Thr5481Met | missense_variant | 41/49 | 5 | NM_002458.3 | P1 | |
MUC5B | ENST00000526859.1 | c.77C>T | p.Thr26Met | missense_variant | 1/6 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000212 AC: 35AN: 164856Hom.: 0 AF XY: 0.000190 AC XY: 17AN XY: 89486
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GnomAD4 exome AF: 0.000245 AC: 344AN: 1402374Hom.: 1 Cov.: 33 AF XY: 0.000222 AC XY: 154AN XY: 694158
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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 | Apr 15, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Thr5481Met va riant in MUC5B has not been previously reported in individuals with pulmonary di sease, but has been identified in 5/14014 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369142865). Threonine (Thr) at position 5481 is not conserved in mammals or evolutionarily distant species and 3 species (guinea pig, pacific walrus, and painted turtle) c arry a methionine (Met) at this position, supporting that this change may be tol erated. Additional computational prediction tools suggest that the p.Thr5481Met variant may not impact the protein, though this information is not predictive en ough to rule out pathogenicity. In summary, while the clinical significance of t he p.Thr5481Met variant is uncertain, the presence of the variant amino acid in other mammals suggests that it is more likely to be benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Vest4
MVP
ClinPred
T
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