Genetic Variant NM_002458.3:c.13124C>A (chr11-1250004-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002458.3(MUC5B):c.13124C>A(p.Ala4375Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,611,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4375V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08433673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.13124C>A	p.Ala4375Asp	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>A	p.Ala4375Asp	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.0000530

AC:

AN:

151084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000889

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

245546

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000548

AC:

AN:

1460684

Hom.:

Cov.:

120

AF XY:

0.0000454

AC XY:

AN XY:

726606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000666

AC:

AN:

1111260

Other (OTH)

AF:

0.0000995

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000530

AC:

AN:

151084

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73718

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41264

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000889

AC:

AN:

67522

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000128

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.4

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.032

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.66

M_CAP

Benign

0.0016

MetaRNN

Benign

0.084

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

-7.6

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.78

REVEL

Benign

0.038

Sift

Uncertain

0.013

Vest4

0.081

MVP

0.043

ClinPred

0.055

GERP RS

-3.4

Varity_R

0.13

gMVP

0.45

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over