11-1226252-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002458.3(MUC5B):​c.175G>T​(p.Val59Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.18

Publications

0 publications found
Variant links:
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]
MUC5B Gene-Disease associations (from GenCC):
  • interstitial lung disease
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06547937).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUC5BNM_002458.3 linkc.175G>T p.Val59Phe missense_variant Exon 3 of 49 ENST00000529681.5 NP_002449.2 Q9HC84

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MUC5BENST00000529681.5 linkc.175G>T p.Val59Phe missense_variant Exon 3 of 49 5 NM_002458.3 ENSP00000436812.1 Q9HC84
MUC5BENST00000525715.5 linkn.233G>T non_coding_transcript_exon_variant Exon 3 of 26 1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
7.12e-7
AC:
1
AN:
1404652
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
693736
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
31764
American (AMR)
AF:
0.00
AC:
0
AN:
36824
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25284
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35974
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79514
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47254
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5712
European-Non Finnish (NFE)
AF:
9.23e-7
AC:
1
AN:
1084002
Other (OTH)
AF:
0.00
AC:
0
AN:
58324
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
34
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 25, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.175G>T (p.V59F) alteration is located in exon 3 (coding exon 3) of the MUC5B gene. This alteration results from a G to T substitution at nucleotide position 175, causing the valine (V) at amino acid position 59 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.12
DANN
Benign
0.79
DEOGEN2
Benign
0.017
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.065
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N
PhyloP100
-3.2
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.073
Sift
Benign
0.032
D
Polyphen
0.45
B
Vest4
0.17
MutPred
0.24
Loss of glycosylation at S54 (P = 0.1172);
MVP
0.043
ClinPred
0.10
T
GERP RS
-6.5
Varity_R
0.089
gMVP
0.90
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs746333758; hg19: chr11-1247482; API