11-1247283-G-C

Variant names:

• chr11-1247283-G-C
• rs2943529
• NM_002458.3:c.10403G>C

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.10403G>C​(p.Arg3468Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,599,462 control chromosomes in the GnomAD database, including 187,111 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 the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3468C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (17280 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169831 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.88

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:53936): (MUC5B antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.8240413E-6).
• BP6: Variant 11-1247283-G-C is Benign according to our data. Variant chr11-1247283-G-C is described in ClinVar as [Benign]. Clinvar id is 403161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.10403G>C	p.Arg3468Pro	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+2338C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.10403G>C	p.Arg3468Pro	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+2338C>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.472 AC: 70378 AN: 149252 Hom.: 17259 Cov.: 32

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.485

GnomAD3 exomes AF: 0.505 AC: 123513 AN: 244588 Hom.: 32678 AF XY: 0.497 AC XY: 66120 AN XY: 132932

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.661

Gnomad SAS exome AF: 0.435

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.493

GnomAD4 exome AF: 0.478 AC: 692579 AN: 1450090 Hom.: 169831 Cov.: 192 AF XY: 0.475 AC XY: 342928 AN XY: 721336

Gnomad4 AFR exome AF: 0.389

Gnomad4 AMR exome AF: 0.591

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.705

Gnomad4 SAS exome AF: 0.435

Gnomad4 FIN exome AF: 0.561

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.473

GnomAD4 genome AF: 0.472 AC: 70430 AN: 149372 Hom.: 17280 Cov.: 32 AF XY: 0.479 AC XY: 34945 AN XY: 72946

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.663

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.490

Alfa AF: 0.397 Hom.: 1967

Bravo AF: 0.470

ESP6500AA AF: 0.383 AC: 1603

ESP6500EA AF: 0.464 AC: 3901

ExAC AF: 0.497 AC: 60089

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.8
DANN	Benign	0.60
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.0060
Sift	Benign	0.17	T
Vest4		0.013
ClinPred		0.0069	T
GERP RS		-0.59
Varity_R		0.10
gMVP		0.32

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: rs2943529; hg19: chr11-1268513; COSMIC: COSV71594280;