Genetic Variant NM_002458.3:c.16660G>A (chr11-1259008-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002458.3(MUC5B):c.16660G>A(p.Asp5554Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,560,460 control chromosomes in the GnomAD database, including 1,401 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 Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 237 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1164 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.46

Publications

12 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=0.0021681786).

BP6

Variant 11-1259008-G-A is Benign according to our data. Variant chr11-1259008-G-A is described in ClinVar as Benign. ClinVar VariationId is 164011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.16660G>A	p.Asp5554Asn	missense	Exon 44 of 49	NP_002449.2	Q9HC84

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.16660G>A	p.Asp5554Asn	missense	Exon 44 of 49	ENSP00000436812.1	Q9HC84
	MUC5B	ENST00000526859.1	TSL:3	c.295G>A	p.Asp99Asn	missense	Exon 4 of 6	ENSP00000434539.1	H0YDX8

Frequencies

GnomAD3 genomes

AF:

0.0485

AC:

7372

AN:

152012

Hom.:

234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0935

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.0327

Gnomad ASJ

AF:

0.0764

Gnomad EAS

AF:

0.00309

Gnomad SAS

AF:

0.0658

Gnomad FIN

AF:

0.00839

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0321

Gnomad OTH

AF:

0.0464

GnomAD2 exomes

AF:

0.0375

AC:

6415

AN:

171098

AF XY:

0.0396

show subpopulations

Gnomad AFR exome

AF:

0.0988

Gnomad AMR exome

AF:

0.0227

Gnomad ASJ exome

AF:

0.0877

Gnomad EAS exome

AF:

0.00324

Gnomad FIN exome

AF:

0.00928

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0428

GnomAD4 exome

AF:

0.0359

AC:

50572

AN:

1408330

Hom.:

1164

Cov.:

AF XY:

0.0371

AC XY:

25795

AN XY:

695514

show subpopulations

African (AFR)

AF:

0.101

AC:

3231

AN:

31878

American (AMR)

AF:

0.0250

AC:

929

AN:

37224

Ashkenazi Jewish (ASJ)

AF:

0.0834

AC:

2105

AN:

25228

East Asian (EAS)

AF:

0.00212

AC:

AN:

36352

South Asian (SAS)

AF:

0.0705

AC:

5617

AN:

79622

European-Finnish (FIN)

AF:

0.0101

AC:

492

AN:

48564

Middle Eastern (MID)

AF:

0.0778

AC:

444

AN:

5704

European-Non Finnish (NFE)

AF:

0.0324

AC:

35214

AN:

1085270

Other (OTH)

AF:

0.0421

AC:

2463

AN:

58488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2756

5512

8268

11024

13780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1454

2908

4362

5816

7270

<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:

0.0486

AC:

7390

AN:

152130

Hom.:

237

Cov.:

AF XY:

0.0472

AC XY:

3510

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0939

AC:

3893

AN:

41476

American (AMR)

AF:

0.0327

AC:

500

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0764

AC:

265

AN:

3470

East Asian (EAS)

AF:

0.00309

AC:

AN:

5172

South Asian (SAS)

AF:

0.0650

AC:

314

AN:

4828

European-Finnish (FIN)

AF:

0.00839

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0321

AC:

2181

AN:

67964

Other (OTH)

AF:

0.0449

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

354

708

1062

1416

1770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0381

Hom.:

408

Bravo

AF:

0.0520

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0327

AC:

126

ESP6500AA

AF:

0.0845

AC:

329

ESP6500EA

AF:

0.0301

AC:

247

ExAC

AF:

0.0239

AC:

2681

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MUC5B-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.3

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.016

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.71

PhyloP100

-1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.2

REVEL

Benign

0.019

Sift

Benign

0.30

Sift4G

Benign

0.44

Vest4

0.015

ClinPred

0.0027

GERP RS

1.6

Varity_R

0.041

gMVP

0.89

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over