11-1257566-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.16306G>A(p.Val5436Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,607,968 control chromosomes in the GnomAD database, including 884 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 0.023 ( 57 hom., cov: 32)

Exomes 𝑓: 0.030 ( 827 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.00300

Publications

10 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=0.0031365752).

BP6

Variant 11-1257566-G-A is Benign according to our data. Variant chr11-1257566-G-A is described in ClinVar as Benign. ClinVar VariationId is 164009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0228 (3479/152290) while in subpopulation NFE AF = 0.0328 (2228/68016). AF 95% confidence interval is 0.0316. There are 57 homozygotes in GnomAd4. There are 1737 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.16306G>A	p.Val5436Met	missense_variant	Exon 41 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.16306G>A	p.Val5436Met	missense_variant	Exon 41 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B	ENST00000526859.1 link	c.-60G>A		upstream_gene_variant		3		ENSP00000434539.1		H0YDX8

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3479

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00557

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00809

Gnomad FIN

AF:

0.0690

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0328

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0254

AC:

6197

AN:

243876

AF XY:

0.0254

show subpopulations

Gnomad AFR exome

AF:

0.00634

Gnomad AMR exome

AF:

0.00485

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0740

Gnomad NFE exome

AF:

0.0345

Gnomad OTH exome

AF:

0.0271

GnomAD4 exome

AF:

0.0298

AC:

43348

AN:

1455678

Hom.:

827

Cov.:

AF XY:

0.0292

AC XY:

21121

AN XY:

724348

show subpopulations

African (AFR)

AF:

0.00391

AC:

131

AN:

33474

American (AMR)

AF:

0.00521

AC:

233

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0292

AC:

762

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00952

AC:

821

AN:

86246

European-Finnish (FIN)

AF:

0.0718

AC:

3427

AN:

47706

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0327

AC:

36319

AN:

1111670

Other (OTH)

AF:

0.0270

AC:

1628

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2524

5047

7571

10094

12618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1330

2660

3990

5320

6650

<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:

0.0228

AC:

3479

AN:

152290

Hom.:

Cov.:

AF XY:

0.0233

AC XY:

1737

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00556

AC:

231

AN:

41566

American (AMR)

AF:

0.00686

AC:

105

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00809

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0690

AC:

733

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0328

AC:

2228

AN:

68016

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

181

361

542

722

903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0288

Hom.:

199

Bravo

AF:

0.0172

TwinsUK

AF:

0.0302

AC:

112

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00746

AC:

ESP6500EA

AF:

0.0317

AC:

269

ExAC

AF:

0.0270

AC:

3256

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0252

EpiControl

AF:

0.0264

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Val5436Met in exon 41 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 3.2% (269/8482) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs55657020). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.021

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

-0.0030

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

REVEL

Benign

0.037

Sift

Benign

0.12

Vest4

0.10

ClinPred

0.0092

GERP RS

0.71

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.042

gMVP

0.58

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over