rs117860519

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002458.3(MUC5B):c.15218-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,610,218 control chromosomes in the GnomAD database, including 902 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 64 hom., cov: 33)

Exomes 𝑓: 0.030 ( 838 hom. )

Consequence

MUC5B
NM_002458.3 splice_region, intron

Scores

Splicing: ADA: 0.00002709

Clinical Significance

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

Conservation

PhyloP100: -2.37

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 11-1254088-G-A is Benign according to our data. Variant chr11-1254088-G-A is described in ClinVar as Benign. ClinVar VariationId is 178791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0255 (3882/152274) while in subpopulation NFE AF = 0.0327 (2225/68018). AF 95% confidence interval is 0.0316. There are 64 homozygotes in GnomAd4. There are 1927 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.15218-4G>A		splice_region_variant, intron_variant	Intron 33 of 48	ENST00000529681.5	NP_002449.2	Q9HC84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.15218-4G>A		splice_region_variant, intron_variant	Intron 33 of 48	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.0255

AC:

3883

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0268

AC:

6542

AN:

244538

AF XY:

0.0265

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.00525

Gnomad ASJ exome

AF:

0.0284

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.0759

Gnomad NFE exome

AF:

0.0345

Gnomad OTH exome

AF:

0.0284

GnomAD4 exome

AF:

0.0302

AC:

44007

AN:

1457944

Hom.:

838

Cov.:

AF XY:

0.0295

AC XY:

21425

AN XY:

725336

show subpopulations

African (AFR)

AF:

0.0143

AC:

479

AN:

33458

American (AMR)

AF:

0.00576

AC:

257

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.0292

AC:

761

AN:

26100

East Asian (EAS)

AF:

0.000151

AC:

AN:

39674

South Asian (SAS)

AF:

0.00954

AC:

822

AN:

86126

European-Finnish (FIN)

AF:

0.0731

AC:

3700

AN:

50606

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0326

AC:

36281

AN:

1111320

Other (OTH)

AF:

0.0278

AC:

1674

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2530

5059

7589

10118

12648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1336

2672

4008

5344

6680

<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:

0.0255

AC:

3882

AN:

152274

Hom.:

Cov.:

AF XY:

0.0259

AC XY:

1927

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0148

AC:

617

AN:

41552

American (AMR)

AF:

0.00771

AC:

118

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00807

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0692

AC:

734

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0327

AC:

2225

AN:

68018

Other (OTH)

AF:

0.0223

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

188

377

565

754

942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0290

Hom.:

Bravo

AF:

0.0205

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0265

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

15218-4G>A in intron 33 of MUC5B: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 3.2% (268/8444) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs117860519). -

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

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.018

(source)

DANN

Benign

0.57

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0

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