11-1246458-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/18 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

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 made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3801 AD 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

GnomAD3 exomes

AF:

0.0247

AC:

6129

AN:

247974

Hom.:

149

AF XY:

0.0247

AC XY:

3320

AN XY:

134602

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 SAS exome

AF:

0.00912

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

Gnomad4 AFR exome

AF:

0.0113

Gnomad4 AMR exome

AF:

0.00539

Gnomad4 ASJ exome

AF:

0.0282

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00913

Gnomad4 FIN exome

AF:

0.0713

Gnomad4 NFE exome

AF:

0.0299

Gnomad4 OTH exome

AF:

0.0259

GnomAD4 genome

AF:

0.0262

AC:

3801

AN:

145264

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

1889

AN XY:

71058

show subpopulations

Gnomad4 AFR

AF:

0.0139

Gnomad4 AMR

AF:

0.00788

Gnomad4 ASJ

AF:

0.0304

Gnomad4 EAS

AF:

0.000212

Gnomad4 SAS

AF:

0.00881

Gnomad4 FIN

AF:

0.0717

Gnomad4 NFE

AF:

0.0338

Gnomad4 OTH

AF:

0.0236

Alfa

AF:

0.0357

Hom.:

364

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

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

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

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