chr11-1250631-C-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.13751C>T(p.Thr4584Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 150,794 control chromosomes in the GnomAD database, including 1 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 0.020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.027 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00800

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 (0.0244) population. However there is too low homozygotes in high coverage region: (expected more than 14, got 1).

BP4

Computational evidence support a benign effect (MetaRNN=0.0036872923).

BP6

Variant 11-1250631-C-T is Benign according to our data. Variant chr11-1250631-C-T is described in ClinVar as [Benign]. Clinvar id is 403177.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.13751C>T	p.Thr4584Ile	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.13751C>T	p.Thr4584Ile	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

2991

AN:

150674

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00630

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00666

Gnomad FIN

AF:

0.0545

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0178

GnomAD2 exomes

AF:

0.0227

AC:

5588

AN:

246662

AF XY:

0.0228

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.00404

Gnomad ASJ exome

AF:

0.0254

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0676

Gnomad NFE exome

AF:

0.0288

Gnomad OTH exome

AF:

0.0218

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0270

AC:

39228

AN:

1453506

Hom.:

Cov.:

151

AF XY:

0.0263

AC XY:

19036

AN XY:

722996

show subpopulations

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

African (AFR)

AF:

0.0113

AC:

379

AN:

33416

American (AMR)

AF:

0.00464

AC:

207

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.0255

AC:

661

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00834

AC:

718

AN:

86078

European-Finnish (FIN)

AF:

0.0618

AC:

3232

AN:

52314

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0295

AC:

32566

AN:

1105680

Other (OTH)

AF:

0.0240

AC:

1438

AN:

59994

⚠️ 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: 0.282

Heterozygous variant carriers

3676

7352

11028

14704

18380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0198

AC:

2991

AN:

150794

Hom.:

Cov.:

AF XY:

0.0199

AC XY:

1466

AN XY:

73656

show subpopulations

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

African (AFR)

AF:

0.0117

AC:

486

AN:

41402

American (AMR)

AF:

0.00630

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00687

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.0545

AC:

564

AN:

10342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0254

AC:

1703

AN:

67102

Other (OTH)

AF:

0.0177

AC:

AN:

2096

⚠️ 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: 0.331

Heterozygous variant carriers

154

309

463

618

772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0286

Hom.:

ExAC

AF:

0.0259

AC:

3129

ClinVar

Significance: 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: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: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

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.6

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.025

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

0.0080

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.69

REVEL

Benign

0.015

Sift

Uncertain

0.024

Vest4

0.041

ClinPred

0.0012

GERP RS

-1.7

Varity_R

0.033

gMVP

0.17

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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chr11-1250631-C-T

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