11-1246061-T-C

Position:

chr11-1246061-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.9181T>C(p.Ser3061Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 148,444 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 78 hom., cov: 29)

Exomes 𝑓: 0.030 ( 923 hom. )

Failed GnomAD Quality Control

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.55

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=0.0034552217).

BP6

Variant 11-1246061-T-C is Benign according to our data. Variant chr11-1246061-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 403189.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 = 0.0257 (3816/148444) while in subpopulation NFE AF= 0.0332 (2228/67054). AF 95% confidence interval is 0.0321. There are 78 homozygotes in gnomad4. There are 1898 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3816 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3 linkuse as main transcript	c.9181T>C	p.Ser3061Pro	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1 linkuse as main transcript	n.57-3423A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 linkuse as main transcript	c.9181T>C	p.Ser3061Pro	missense_variant	31/49	5	NM_002458.3	ENSP00000436812	P1
MUC5B-AS1	ENST00000532061.2 linkuse as main transcript	n.57-3423A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0257

AC:

3817

AN:

148324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00767

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000204

Gnomad SAS

AF:

0.00842

Gnomad FIN

AF:

0.0712

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0332

Gnomad OTH

AF:

0.0226

GnomAD3 exomes

AF:

0.0267

AC:

6661

AN:

249048

Hom.:

154

AF XY:

0.0265

AC XY:

3585

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.00513

Gnomad ASJ exome

AF:

0.0289

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00941

Gnomad FIN exome

AF:

0.0745

Gnomad NFE exome

AF:

0.0345

Gnomad OTH exome

AF:

0.0280

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0302

AC:

44128

AN:

1461450

Hom.:

923

Cov.:

AF XY:

0.0295

AC XY:

21483

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0121

Gnomad4 AMR exome

AF:

0.00575

Gnomad4 ASJ exome

AF:

0.0294

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00953

Gnomad4 FIN exome

AF:

0.0729

Gnomad4 NFE exome

AF:

0.0326

Gnomad4 OTH exome

AF:

0.0276

GnomAD4 genome

AF:

0.0257

AC:

3816

AN:

148444

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1898

AN XY:

72400

show subpopulations

Gnomad4 AFR

AF:

0.0137

Gnomad4 AMR

AF:

0.00766

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.000204

Gnomad4 SAS

AF:

0.00843

Gnomad4 FIN

AF:

0.0712

Gnomad4 NFE

AF:

0.0332

Gnomad4 OTH

AF:

0.0224

Alfa

AF:

0.0300

Hom.:

Bravo

AF:

0.0200

ESP6500AA

AF:

0.0122

AC:

ESP6500EA

AF:

0.0239

AC:

201

ExAC

AF:

0.0279

AC:

3382

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0070

DANN

Benign

0.41

DEOGEN2

Benign

0.035

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.68

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.78

REVEL

Benign

0.016

Sift

Benign

0.26

Vest4

0.020

ClinPred

0.0085

GERP RS

-6.4

Varity_R

0.061

gMVP

0.14

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