NM_002458.3:c.14573T>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002458.3(MUC5B):c.14573T>C(p.Met4858Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,546,162 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M4858L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.15

Publications

4 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

MUC5B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007142365).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.14573T>C	p.Met4858Thr	missense	Exon 31 of 49	NP_002449.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.14573T>C	p.Met4858Thr	missense	Exon 31 of 49	ENSP00000436812.1

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

143994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.000305

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000740

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000996

AC:

238

AN:

239004

AF XY:

0.000909

show subpopulations

Gnomad AFR exome

AF:

0.000332

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00976

Gnomad NFE exome

AF:

0.000365

Gnomad OTH exome

AF:

0.000690

GnomAD4 exome

AF:

0.0000941

AC:

132

AN:

1402168

Hom.:

Cov.:

AF XY:

0.0000959

AC XY:

AN XY:

698806

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000606

AC:

AN:

33004

American (AMR)

AF:

0.0000225

AC:

AN:

44362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25374

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

85548

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

49728

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000424

AC:

AN:

1060354

Other (OTH)

AF:

0.0000171

AC:

AN:

58374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.290

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000618

AC:

AN:

143994

Hom.:

Cov.:

AF XY:

0.000683

AC XY:

AN XY:

70260

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000449

AC:

AN:

40054

American (AMR)

AF:

0.000200

AC:

AN:

14966

Ashkenazi Jewish (ASJ)

AF:

0.000305

AC:

AN:

3274

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4682

European-Finnish (FIN)

AF:

0.00218

AC:

AN:

9178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000740

AC:

AN:

63538

Other (OTH)

AF:

0.00

AC:

AN:

1980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00744

Hom.:

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0153

AC:

ExAC

AF:

0.00175

AC:

212

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: One risk variant in this gene has been associated with pulmonary fibrosis

Interstitial lung disease 2

Uncertain:1

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.047

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.016

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.26

M_CAP

Benign

0.0011

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.0

PhyloP100

-1.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.19

REVEL

Benign

0.028

Sift

Benign

0.50

Vest4

0.031

MVP

0.043

ClinPred

0.0049

GERP RS

1.3

Varity_R

0.033

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over