11-1246458-T-C

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.9578T>C(p.Leu3193Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,599,640 control chromosomes in the GnomAD database, including 968 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 74 hom., cov: 32)

Exomes 𝑓: 0.028 ( 894 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.873

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002866596).

BP6

Variant 11-1246458-T-C is Benign according to our data. Variant chr11-1246458-T-C is described in ClinVar as [Benign]. Clinvar id is 403153.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 = 0.0262 (3801/145264) while in subpopulation NFE AF = 0.0338 (2217/65620). AF 95% confidence interval is 0.0326. There are 74 homozygotes in GnomAd4. There are 1889 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 74 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.9578T>C	p.Leu3193Pro	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2	Q9HC84
MUC5B-AS1	NR_157183.1 link	n.56+3163A>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.9578T>C	p.Leu3193Pro	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B-AS1	ENST00000532061.2 link	n.56+3163A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3802

AN:

145142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.00113

Gnomad AMR

AF:

0.00789

Gnomad ASJ

AF:

0.0304

Gnomad EAS

AF:

0.000212

Gnomad SAS

AF:

0.00879

Gnomad FIN

AF:

0.0717

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0338

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0247

AC:

6129

AN:

247974

AF XY:

0.0247

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.00487

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0707

Gnomad NFE exome

AF:

0.0317

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0279

AC:

40542

AN:

1454376

Hom.:

894

Cov.:

127

AF XY:

0.0274

AC XY:

19808

AN XY:

723712

show subpopulations

African (AFR)

AF:

0.0113

AC:

378

AN:

33434

American (AMR)

AF:

0.00539

AC:

241

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

736

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00913

AC:

787

AN:

86168

European-Finnish (FIN)

AF:

0.0713

AC:

3789

AN:

53158

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0299

AC:

33024

AN:

1105266

Other (OTH)

AF:

0.0259

AC:

1560

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.598

Heterozygous variant carriers

2990

5979

8969

11958

14948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0262

AC:

3801

AN:

145264

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

1889

AN XY:

71058

show subpopulations

African (AFR)

AF:

0.0139

AC:

542

AN:

39010

American (AMR)

AF:

0.00788

AC:

116

AN:

14728

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

102

AN:

3360

East Asian (EAS)

AF:

0.000212

AC:

AN:

4714

South Asian (SAS)

AF:

0.00881

AC:

AN:

4428

European-Finnish (FIN)

AF:

0.0717

AC:

736

AN:

10264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0338

AC:

2217

AN:

65620

Other (OTH)

AF:

0.0236

AC:

AN:

1992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.573

Heterozygous variant carriers

169

337

506

674

843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.209

Hom.:

7672

Bravo

AF:

0.0200

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0300

AC:

254

ExAC

AF:

0.0239

AC:

2890

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

0.045

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.33

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.028

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00072

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.81

PhyloP100

-0.87

PrimateAI

Benign

0.22

PROVEAN

Benign

0.85

REVEL

Benign

0.013

Sift

Benign

0.18

Vest4

0.0090

ClinPred

0.0082

Varity_R

0.057

gMVP

0.21

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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11-1246458-T-C

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