rs191989562

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_002458.3(MUC5B):c.14584G>A(p.Gly4862Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,544,840 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4862D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.656

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056443214).

BP6

Variant 11-1251464-G-A is Benign according to our data. Variant chr11-1251464-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 403196.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.14584G>A	p.Gly4862Ser	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.14584G>A	p.Gly4862Ser	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.000660

AC:

AN:

143874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000500

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000200

Gnomad ASJ

AF:

0.000306

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00229

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000788

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00150

AC:

356

AN:

237108

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.000333

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.000869

GnomAD4 exome

AF:

0.000139

AC:

195

AN:

1400966

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

697968

show subpopulations

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

African (AFR)

AF:

0.0000606

AC:

AN:

32990

American (AMR)

AF:

0.00

AC:

AN:

44312

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25316

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000351

AC:

AN:

85420

European-Finnish (FIN)

AF:

0.00181

AC:

AN:

49624

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000897

AC:

AN:

1059538

Other (OTH)

AF:

0.0000514

AC:

AN:

58342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.302

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:

0.000660

AC:

AN:

143874

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

AN XY:

70184

show subpopulations

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

African (AFR)

AF:

0.000500

AC:

AN:

40040

American (AMR)

AF:

0.000200

AC:

AN:

14986

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

3268

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4656

European-Finnish (FIN)

AF:

0.00229

AC:

AN:

9166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000788

AC:

AN:

63456

Other (OTH)

AF:

0.00

AC:

AN:

1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.368

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:

0.0112

Hom.:

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0218

AC:

ExAC

AF:

0.00177

AC:

215

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

0.076

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.54

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.020

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0081

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

-0.66

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.61

REVEL

Benign

0.078

Sift

Benign

0.40

Vest4

0.060

MVP

0.11

ClinPred

0.0067

GERP RS

-3.8

Varity_R

0.031

gMVP

0.19

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