rs188444809

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_002458.3(MUC5B):c.13924A>G(p.Ile4642Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,443,452 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.024 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.83

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: Benign. The variant received -10 ACMG points.

PM2

Variant has high frequency in the NFE (0.0265) population. However there is too low homozygotes in high coverage region: (expected more than 203, got 1).

BP4

Computational evidence support a benign effect (MetaRNN=0.0040473044).

BP6

Variant 11-1250804-A-G is Benign according to our data. Variant chr11-1250804-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 403193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.13924A>G	p.Ile4642Val	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.13924A>G	p.Ile4642Val	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.00853

AC:

1260

AN:

147756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00708

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00232

Gnomad ASJ

AF:

0.00626

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00210

Gnomad FIN

AF:

0.0269

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00956

Gnomad OTH

AF:

0.00689

GnomAD2 exomes

AF:

0.0166

AC:

4033

AN:

242864

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00887

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.0205

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0529

Gnomad NFE exome

AF:

0.0205

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0237

AC:

34256

AN:

1443452

Hom.:

Cov.:

155

AF XY:

0.0231

AC XY:

16574

AN XY:

717992

show subpopulations

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

African (AFR)

AF:

0.00987

AC:

329

AN:

33340

American (AMR)

AF:

0.00377

AC:

168

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

458

AN:

25538

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00643

AC:

551

AN:

85726

European-Finnish (FIN)

AF:

0.0424

AC:

2125

AN:

50150

Middle Eastern (MID)

AF:

0.00298

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0268

AC:

29463

AN:

1099378

Other (OTH)

AF:

0.0192

AC:

1143

AN:

59386

⚠️ 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: 0.335

Heterozygous variant carriers

2738

5476

8215

10953

13691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00852

AC:

1260

AN:

147878

Hom.:

Cov.:

AF XY:

0.00864

AC XY:

624

AN XY:

72222

show subpopulations

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

African (AFR)

AF:

0.00704

AC:

289

AN:

41064

American (AMR)

AF:

0.00231

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00626

AC:

AN:

3356

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00231

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.0269

AC:

264

AN:

9802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00957

AC:

625

AN:

65340

Other (OTH)

AF:

0.00682

AC:

AN:

2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.293

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0162

Hom.:

ESP6500AA

AF:

0.0101

AC:

ESP6500EA

AF:

0.0198

AC:

167

ExAC

AF:

0.0236

AC:

2853

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

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: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.017

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.018

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

-4.8

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.020

REVEL

Benign

0.020

Sift

Benign

0.57

Vest4

0.059

ClinPred

0.0049

GERP RS

-3.1

Varity_R

0.019

gMVP

0.091

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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rs188444809

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over