11-1248442-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002458.3(MUC5B):c.11562T>C(p.Ser3854Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,551,570 control chromosomes in the GnomAD database, including 213,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19263 hom., cov: 27)

Exomes 𝑓: 0.50 ( 194203 hom. )

Consequence

MUC5B
NM_002458.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -6.02

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BP6

Variant 11-1248442-T-C is Benign according to our data. Variant chr11-1248442-T-C is described in ClinVar as Benign. ClinVar VariationId is 403169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.11562T>C	p.Ser3854Ser	synonymous_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1 link	n.56+1179A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.11562T>C	p.Ser3854Ser	synonymous_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2 link	n.56+1179A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

73405

AN:

145568

Hom.:

19241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.450

Gnomad AMI

AF:

0.544

Gnomad AMR

AF:

0.578

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.668

Gnomad SAS

AF:

0.508

Gnomad FIN

AF:

0.568

Gnomad MID

AF:

0.523

Gnomad NFE

AF:

0.495

Gnomad OTH

AF:

0.518

GnomAD2 exomes

AF:

0.519

AC:

118570

AN:

228508

AF XY:

0.513

show subpopulations

Gnomad AFR exome

AF:

0.413

Gnomad AMR exome

AF:

0.622

Gnomad ASJ exome

AF:

0.519

Gnomad EAS exome

AF:

0.666

Gnomad FIN exome

AF:

0.540

Gnomad NFE exome

AF:

0.481

Gnomad OTH exome

AF:

0.515

GnomAD4 exome

AF:

0.501

AC:

703882

AN:

1405874

Hom.:

194203

Cov.:

117

AF XY:

0.500

AC XY:

349950

AN XY:

699894

show subpopulations

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

African (AFR)

AF:

0.439

AC:

14126

AN:

32156

American (AMR)

AF:

0.613

AC:

26472

AN:

43166

Ashkenazi Jewish (ASJ)

AF:

0.523

AC:

13156

AN:

25140

East Asian (EAS)

AF:

0.707

AC:

28037

AN:

39644

South Asian (SAS)

AF:

0.501

AC:

41777

AN:

83328

European-Finnish (FIN)

AF:

0.550

AC:

28528

AN:

51854

Middle Eastern (MID)

AF:

0.516

AC:

2830

AN:

5484

European-Non Finnish (NFE)

AF:

0.487

AC:

519675

AN:

1066872

Other (OTH)

AF:

0.503

AC:

29281

AN:

58230

⚠️ 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: 0.358

Heterozygous variant carriers

17310

34620

51930

69240

86550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14652

29304

43956

58608

73260

<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:

0.504

AC:

73473

AN:

145696

Hom.:

19263

Cov.:

AF XY:

0.510

AC XY:

36214

AN XY:

70988

show subpopulations

African (AFR)

AF:

0.450

AC:

17856

AN:

39678

American (AMR)

AF:

0.579

AC:

8648

AN:

14940

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

1789

AN:

3352

East Asian (EAS)

AF:

0.668

AC:

3347

AN:

5010

South Asian (SAS)

AF:

0.507

AC:

2335

AN:

4606

European-Finnish (FIN)

AF:

0.568

AC:

5483

AN:

9660

Middle Eastern (MID)

AF:

0.507

AC:

144

AN:

284

European-Non Finnish (NFE)

AF:

0.496

AC:

32343

AN:

65272

Other (OTH)

AF:

0.521

AC:

1043

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1559

3118

4678

6237

7796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<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:

0.493

Hom.:

3598

Bravo

AF:

0.502

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.3

(source)

DANN

Benign

0.55

PhyloP100

-6.0

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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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