NM_002458.3:c.15478-13T>C

Variant names:

• chr11-1254681-T-C
• rs56141203
• NM_002458.3:c.15478-13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.15478-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,607,834 control chromosomes in the GnomAD database, including 895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 33)
  • Exomes 𝑓: 0.030 (832 hom.)
• Consequence: MUC5B NM_002458.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.11
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• interstitial lung disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-1254681-T-C is Benign according to our data. Variant chr11-1254681-T-C is described in ClinVar as Benign. ClinVar VariationId is 164003.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 = 0.025 (3807/152314) while in subpopulation NFE AF = 0.0328 (2228/68014). AF 95% confidence interval is 0.0316. There are 63 homozygotes in GnomAd4. There are 1892 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.15478-13T>C		intron_variant	Intron 34 of 48	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.15478-13T>C		intron_variant	Intron 34 of 48	5	NM_002458.3	ENSP00000436812.1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3808 AN: 152196 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0266 AC: 6521 AN: 245246 AF XY: 0.0265

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00508

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0743

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0301 AC: 43781 AN: 1455520 Hom.: 832 Cov.: 34 AF XY: 0.0294 AC XY: 21278 AN XY: 723154

African (AFR) AF: 0.0118 AC: 396 AN: 33420

American (AMR) AF: 0.00560 AC: 249 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 757 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00948 AC: 814 AN: 85908

European-Finnish (FIN) AF: 0.0726 AC: 3788 AN: 52206

Middle Eastern (MID) AF: 0.00470 AC: 27 AN: 5746

European-Non Finnish (NFE) AF: 0.0326 AC: 36099 AN: 1108080

Other (OTH) AF: 0.0275 AC: 1651 AN: 60128

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152314 Hom.: 63 Cov.: 33 AF XY: 0.0254 AC XY: 1892 AN XY: 74468

African (AFR) AF: 0.0131 AC: 543 AN: 41560

American (AMR) AF: 0.00745 AC: 114 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4832

European-Finnish (FIN) AF: 0.0692 AC: 735 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0328 AC: 2228 AN: 68014

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0288 Hom.: 85

Bravo AF: 0.0199

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

15478-13T>C in intron 34 of MUC5B: This variant is not expected to have clinical significance because it has been identified in 3.0% (253/8296) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs56141203).

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.40
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56141203; hg19: chr11-1275911;