chr11-1245890-G-A

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.9010G>A(p.Ala3004Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,612,868 control chromosomes in the GnomAD database, including 287 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 10 hom., cov: 29)

Exomes 𝑓: 0.030 ( 277 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.876

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030438304).

BP6

Variant 11-1245890-G-A is Benign according to our data. Variant chr11-1245890-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 403185.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 = 0.0247 (3739/151410) while in subpopulation NFE AF = 0.0324 (2203/67902). AF 95% confidence interval is 0.0313. There are 10 homozygotes in GnomAd4. There are 1860 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.9010G>A	p.Ala3004Thr	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.57-3252C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.9010G>A	p.Ala3004Thr	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.57-3252C>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3740

AN:

151290

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00742

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.000782

Gnomad SAS

AF:

0.00833

Gnomad FIN

AF:

0.0684

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0324

Gnomad OTH

AF:

0.0216

GnomAD2 exomes

AF:

0.0263

AC:

6558

AN:

249208

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.00519

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0730

Gnomad NFE exome

AF:

0.0340

Gnomad OTH exome

AF:

0.0273

GnomAD4 exome

AF:

0.0298

AC:

43529

AN:

1461458

Hom.:

277

Cov.:

AF XY:

0.0292

AC XY:

21209

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.0112

AC:

376

AN:

33434

American (AMR)

AF:

0.00570

AC:

255

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

761

AN:

26122

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00955

AC:

824

AN:

86246

European-Finnish (FIN)

AF:

0.0719

AC:

3837

AN:

53330

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0322

AC:

35805

AN:

1111786

Other (OTH)

AF:

0.0272

AC:

1639

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

2782

5564

8345

11127

13909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1332

2664

3996

5328

6660

<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:

0.0247

AC:

3739

AN:

151410

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1860

AN XY:

73966

show subpopulations

African (AFR)

AF:

0.0126

AC:

516

AN:

41056

American (AMR)

AF:

0.00741

AC:

113

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3460

East Asian (EAS)

AF:

0.000783

AC:

AN:

5106

South Asian (SAS)

AF:

0.00833

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0684

AC:

721

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0324

AC:

2203

AN:

67902

Other (OTH)

AF:

0.0214

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.587

Heterozygous variant carriers

196

392

588

784

980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0222

Hom.:

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.0334

AC:

283

ExAC

AF:

0.0273

AC:

3312

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

0.068

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.0

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.017

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0076

LIST_S2

Benign

0.10

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

-0.88

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.43

REVEL

Benign

0.012

Sift

Benign

0.26

Vest4

0.087

ClinPred

0.00013

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.026

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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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