rs188370271

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.9143C>T(p.Ala3048Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,589,562 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 (★★).

Frequency

Genomes: 𝑓 0.019 ( 0 hom., cov: 29)

Exomes 𝑓: 0.022 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0550

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 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 -10 ACMG points.

PM2

Variant has high frequency in the NFE (0.0231) population. However there is too low homozygotes in high coverage region: (expected more than 187, got 0).

BP4

Computational evidence support a benign effect (MetaRNN=0.0033162236).

BP6

Variant 11-1246023-C-T is Benign according to our data. Variant chr11-1246023-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 403187.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.9143C>T	p.Ala3048Val	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.57-3385G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.9143C>T	p.Ala3048Val	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.57-3385G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2904

AN:

150380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00539

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00540

Gnomad ASJ

AF:

0.0244

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00628

Gnomad FIN

AF:

0.0579

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0155

GnomAD2 exomes

AF:

0.0221

AC:

5464

AN:

247198

AF XY:

0.0218

show subpopulations

Gnomad AFR exome

AF:

0.00534

Gnomad AMR exome

AF:

0.00418

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0649

Gnomad NFE exome

AF:

0.0293

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0220

AC:

31624

AN:

1439064

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

15605

AN XY:

716476

show subpopulations

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

African (AFR)

AF:

0.00307

AC:

102

AN:

33238

American (AMR)

AF:

0.00428

AC:

191

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.0232

AC:

598

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00753

AC:

647

AN:

85936

European-Finnish (FIN)

AF:

0.0647

AC:

3408

AN:

52704

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0233

AC:

25425

AN:

1091668

Other (OTH)

AF:

0.0207

AC:

1235

AN:

59638

⚠️ 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: 0.263

Heterozygous variant carriers

3292

6584

9876

13168

16460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

842

1684

2526

3368

4210

<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:

0.0193

AC:

2904

AN:

150498

Hom.:

Cov.:

AF XY:

0.0195

AC XY:

1432

AN XY:

73496

show subpopulations

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

African (AFR)

AF:

0.00537

AC:

220

AN:

40970

American (AMR)

AF:

0.00539

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00628

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.0579

AC:

601

AN:

10380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0275

AC:

1854

AN:

67298

Other (OTH)

AF:

0.0153

AC:

AN:

2092

⚠️ 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: 0.311

Heterozygous variant carriers

183

366

549

732

915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

102

136

170

<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:

0.0292

Hom.:

ESP6500AA

AF:

0.00406

AC:

ESP6500EA

AF:

0.0219

AC:

184

ExAC

AF:

0.0267

AC:

3238

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

0.11

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.8

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.036

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

-0.055

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.60

REVEL

Benign

0.033

Sift

Benign

0.15

Vest4

0.0080

ClinPred

0.0054

GERP RS

-1.3

Varity_R

0.026

gMVP

0.15

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