chr11-1246730-A-G

Position:

• chr11-1246730-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.9850A>G​(p.Thr3284Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,591,676 control chromosomes in the GnomAD database, including 475,772 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.81 (50348 hom., cov: 26)
  • Exomes 𝑓: 0.76 (425424 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.681

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6329866E-6).
• BP6: Variant 11-1246730-A-G is Benign according to our data. Variant chr11-1246730-A-G is described in ClinVar as [Benign]. Clinvar id is 403159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.9850A>G	p.Thr3284Ala	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+2891T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.9850A>G	p.Thr3284Ala	missense_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+2891T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.814 AC: 120626 AN: 148106 Hom.: 50278 Cov.: 26

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.818

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.802

GnomAD3 exomes AF: 0.832 AC: 180423 AN: 216836 Hom.: 80065 AF XY: 0.829 AC XY: 96513 AN XY: 116394

Gnomad AFR exome AF: 0.947

Gnomad AMR exome AF: 0.908

Gnomad ASJ exome AF: 0.833

Gnomad EAS exome AF: 0.987

Gnomad SAS exome AF: 0.871

Gnomad FIN exome AF: 0.808

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.756 AC: 1090819 AN: 1443444 Hom.: 425424 Cov.: 128 AF XY: 0.757 AC XY: 543324 AN XY: 717790

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.885

Gnomad4 ASJ exome AF: 0.786

Gnomad4 EAS exome AF: 0.978

Gnomad4 SAS exome AF: 0.834

Gnomad4 FIN exome AF: 0.767

Gnomad4 NFE exome AF: 0.728

Gnomad4 OTH exome AF: 0.784

GnomAD4 genome AF: 0.815 AC: 120759 AN: 148232 Hom.: 50348 Cov.: 26 AF XY: 0.820 AC XY: 59205 AN XY: 72226

Gnomad4 AFR AF: 0.934

Gnomad4 AMR AF: 0.849

Gnomad4 ASJ AF: 0.781

Gnomad4 EAS AF: 0.980

Gnomad4 SAS AF: 0.829

Gnomad4 FIN AF: 0.790

Gnomad4 NFE AF: 0.727

Gnomad4 OTH AF: 0.805

Alfa AF: 0.760 Hom.: 8271

Bravo AF: 0.826

ESP6500AA AF: 0.874 AC: 3386

ESP6500EA AF: 0.580 AC: 4783

ExAC AF: 0.774 AC: 93199

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.30
DEOGEN2	Benign	0.021	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000036	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.6	N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Vest4		0.021
ClinPred		0.00028	T
GERP RS		-4.4
Varity_R		0.017
gMVP		0.15

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

Other links and lift over

dbSNP: rs2943531; hg19: chr11-1267960; COSMIC: COSV71589891;