11-1249847-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002458.3(MUC5B):c.12967G>T(p.Val4323Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 148,352 control chromosomes in the GnomAD database, including 53 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 0.023 ( 53 hom., cov: 31)

Exomes 𝑓: 0.030 ( 859 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: -5.37

Publications

7 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 links:

MUC5B-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

MUC5B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028523505).

BP6

Variant 11-1249847-G-T is Benign according to our data. Variant chr11-1249847-G-T is described in ClinVar as [Benign]. Clinvar id is 403173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.12967G>T	p.Val4323Phe	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.-171C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.12967G>T	p.Val4323Phe	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.-171C>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0235

AC:

3477

AN:

148228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00702

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.00105

Gnomad SAS

AF:

0.00688

Gnomad FIN

AF:

0.0593

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.0176

AC:

4297

AN:

244506

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.00300

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00122

Gnomad FIN exome

AF:

0.0601

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0298

AC:

43537

AN:

1459006

Hom.:

859

Cov.:

107

AF XY:

0.0291

AC XY:

21115

AN XY:

725744

show subpopulations

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

African (AFR)

AF:

0.0127

AC:

423

AN:

33364

American (AMR)

AF:

0.00529

AC:

236

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

689

AN:

25980

East Asian (EAS)

AF:

0.00218

AC:

AN:

39442

South Asian (SAS)

AF:

0.00932

AC:

802

AN:

86058

European-Finnish (FIN)

AF:

0.0716

AC:

3807

AN:

53134

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0323

AC:

35827

AN:

1110386

Other (OTH)

AF:

0.0272

AC:

1641

AN:

60252

⚠️ 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: 0.358

Heterozygous variant carriers

2676

5353

8029

10706

13382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0235

AC:

3479

AN:

148352

Hom.:

Cov.:

AF XY:

0.0239

AC XY:

1730

AN XY:

72372

show subpopulations

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

African (AFR)

AF:

0.0138

AC:

547

AN:

39690

American (AMR)

AF:

0.00702

AC:

106

AN:

15110

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

3438

East Asian (EAS)

AF:

0.00126

AC:

AN:

4764

South Asian (SAS)

AF:

0.00688

AC:

AN:

4648

European-Finnish (FIN)

AF:

0.0593

AC:

610

AN:

10290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0304

AC:

2040

AN:

67158

Other (OTH)

AF:

0.0204

AC:

AN:

2056

⚠️ 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: 0.388

Heterozygous variant carriers

143

285

428

570

713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0179

Hom.:

ExAC

AF:

0.0274

AC:

3325

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

0.074

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.061

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.022

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

-5.4

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.83

REVEL

Benign

0.014

Sift

Benign

0.034

Vest4

0.021

ClinPred

0.0030

GERP RS

-1.5

Varity_R

0.058

gMVP

0.31

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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11-1249847-G-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