chr11-1226857-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002458.3(MUC5B):c.442G>A(p.Val148Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,607,016 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 6 hom., cov: 34)

Exomes 𝑓: 0.0099 ( 93 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.180

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045601726).

BP6

Variant 11-1226857-G-A is Benign according to our data. Variant chr11-1226857-G-A is described in ClinVar as [Benign]. Clinvar id is 163993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00993 (14444/1454958) while in subpopulation MID AF = 0.0248 (143/5766). AF 95% confidence interval is 0.0215. There are 93 homozygotes in GnomAdExome4. There are 7373 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.442G>A	p.Val148Ile	missense_variant	Exon 4 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.442G>A	p.Val148Ile	missense_variant	Exon 4 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B	ENST00000525715.5 link	n.500G>A		non_coding_transcript_exon_variant	Exon 4 of 26	1

Frequencies

GnomAD3 genomes

AF:

0.00838

AC:

1274

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00924

AC:

2206

AN:

238700

AF XY:

0.00943

show subpopulations

Gnomad AFR exome

AF:

0.00224

Gnomad AMR exome

AF:

0.00624

Gnomad ASJ exome

AF:

0.00703

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00986

GnomAD4 exome

AF:

0.00993

AC:

14444

AN:

1454958

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

7373

AN XY:

724028

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33466

American (AMR)

AF:

0.00602

AC:

269

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00793

AC:

207

AN:

26106

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39684

South Asian (SAS)

AF:

0.00752

AC:

648

AN:

86204

European-Finnish (FIN)

AF:

0.0168

AC:

794

AN:

47180

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5766

European-Non Finnish (NFE)

AF:

0.0106

AC:

11803

AN:

1111600

Other (OTH)

AF:

0.00849

AC:

512

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

908

1816

2723

3631

4539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00838

AC:

1275

AN:

152058

Hom.:

Cov.:

AF XY:

0.00844

AC XY:

627

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41498

American (AMR)

AF:

0.00712

AC:

109

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.00665

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0166

AC:

176

AN:

10600

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0120

AC:

814

AN:

67960

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

126

188

251

314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00986

Hom.:

Bravo

AF:

0.00687

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00173

AC:

ESP6500EA

AF:

0.00997

AC:

ExAC

AF:

0.00965

AC:

1163

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00998

EpiControl

AF:

0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MUC5B: BP4, BS1, BS2 -

not specified

Benign:1

May 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val148Ile in exon 4 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 1.2% (795/61246) of European chromo somes, including 6 homozygotes, by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs56293203). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

3.8

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.021

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.1

PhyloP100

-0.18

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.73

REVEL

Benign

0.16

Sift

Benign

0.16

Polyphen

0.0020

Vest4

0.12

MVP

0.12

ClinPred

0.0024

GERP RS

-3.7

Varity_R

0.046

gMVP

0.58

Mutation Taster

=99/1

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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chr11-1226857-G-A

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