rs56232219

Positions:

chr11-1254758-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002458.3(MUC5B):c.15542T>C(p.Leu5181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,612,898 control chromosomes in the GnomAD database, including 904 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 62 hom., cov: 33)

Exomes 𝑓: 0.030 ( 842 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.187

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035450459).

BP6

Variant 11-1254758-T-C is Benign according to our data. Variant chr11-1254758-T-C is described in ClinVar as [Benign]. Clinvar id is 164004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1254758-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3804/152332) while in subpopulation NFE AF= 0.0327 (2225/68016). AF 95% confidence interval is 0.0316. There are 62 homozygotes in gnomad4. There are 1893 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3804 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.15542T>C	p.Leu5181Pro	missense_variant	35/49	ENST00000529681.5	NP_002449.2	Q9HC84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.15542T>C	p.Leu5181Pro	missense_variant	35/49	5	NM_002458.3	ENSP00000436812.1		Q9HC84

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3805

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.0286

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.0691

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0267

AC:

6609

AN:

247776

Hom.:

140

AF XY:

0.0265

AC XY:

3573

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.0152

Gnomad AMR exome

AF:

0.00513

Gnomad ASJ exome

AF:

0.0284

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00941

Gnomad FIN exome

AF:

0.0744

Gnomad NFE exome

AF:

0.0345

Gnomad OTH exome

AF:

0.0279

GnomAD4 exome

AF:

0.0301

AC:

44002

AN:

1460566

Hom.:

842

Cov.:

AF XY:

0.0295

AC XY:

21409

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.0119

Gnomad4 AMR exome

AF:

0.00564

Gnomad4 ASJ exome

AF:

0.0291

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00951

Gnomad4 FIN exome

AF:

0.0726

Gnomad4 NFE exome

AF:

0.0326

Gnomad4 OTH exome

AF:

0.0275

GnomAD4 genome

AF:

0.0250

AC:

3804

AN:

152332

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1893

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0131

Gnomad4 AMR

AF:

0.00745

Gnomad4 ASJ

AF:

0.0286

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00807

Gnomad4 FIN

AF:

0.0691

Gnomad4 NFE

AF:

0.0327

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0294

Hom.:

Bravo

AF:

0.0198

TwinsUK

AF:

0.0302

AC:

112

ALSPAC

AF:

0.0332

AC:

128

ESP6500AA

AF:

0.0153

AC:

ESP6500EA

AF:

0.0321

AC:

273

ExAC

AF:

0.0278

AC:

3357

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Leu5181Pro in exon 35 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 3.2% (273/8496) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs56232219). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.41

DEOGEN2

Benign

0.022

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.57

REVEL

Benign

0.13

Sift

Benign

0.29

Vest4

0.18

ClinPred

0.00015

GERP RS

-0.018

Varity_R

0.066

gMVP

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over