NM_002458.3:c.13124C>T

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.13124C>T(p.Ala4375Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,600,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.026 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -7.65

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 (0.0283) population. However there is too low homozygotes in high coverage region: (expected more than 247, got 0).

BP4

Computational evidence support a benign effect (MetaRNN=0.0036114454).

BP6

Variant 11-1250004-C-T is Benign according to our data. Variant chr11-1250004-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 403191.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.13124C>T	p.Ala4375Val	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.13124C>T	p.Ala4375Val	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2167

AN:

149632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00402

Gnomad ASJ

AF:

0.0165

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00564

Gnomad FIN

AF:

0.0428

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0214

Gnomad OTH

AF:

0.0116

GnomAD2 exomes

AF:

0.0188

AC:

4618

AN:

245546

AF XY:

0.0184

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.00285

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0622

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0259

AC:

37610

AN:

1450250

Hom.:

Cov.:

120

AF XY:

0.0253

AC XY:

18246

AN XY:

721362

show subpopulations

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

African (AFR)

AF:

0.00308

AC:

103

AN:

33406

American (AMR)

AF:

0.00419

AC:

187

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

637

AN:

25880

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00708

AC:

608

AN:

85846

European-Finnish (FIN)

AF:

0.0612

AC:

3194

AN:

52168

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0285

AC:

31484

AN:

1103056

Other (OTH)

AF:

0.0229

AC:

1373

AN:

59876

⚠️ 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: 0.264

Heterozygous variant carriers

3761

7522

11283

15044

18805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1204

2408

3612

4816

6020

<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:

0.0145

AC:

2169

AN:

149756

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1053

AN XY:

73106

show subpopulations

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

African (AFR)

AF:

0.00344

AC:

142

AN:

41288

American (AMR)

AF:

0.00401

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

AN:

3404

East Asian (EAS)

AF:

0.000195

AC:

AN:

5124

South Asian (SAS)

AF:

0.00564

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.0428

AC:

433

AN:

10112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0214

AC:

1425

AN:

66554

Other (OTH)

AF:

0.0115

AC:

AN:

2084

⚠️ 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: 0.294

Heterozygous variant carriers

154

307

461

614

768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

112

140

<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:

0.0229

Hom.:

ESP6500AA

AF:

0.00633

AC:

ESP6500EA

AF:

0.0245

AC:

207

ExAC

AF:

0.0264

AC:

3202

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

0.12

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.17

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.027

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00084

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

PhyloP100

-7.6

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.29

REVEL

Benign

0.032

Sift

Uncertain

0.021

Vest4

0.014

ClinPred

0.0063

GERP RS

-3.4

Varity_R

0.044

gMVP

0.27

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over