chr11-1255193-G-C

Variant names:

• chr11-1255193-G-C
• rs56123928
• NM_002458.3:c.15817G>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.15817G>C​(p.Ala5273Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,487,052 control chromosomes in the GnomAD database, including 826 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (63 hom., cov: 31)
  • Exomes 𝑓: 0.030 (763 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.39
• Publications: 8 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 (MetaRNN=0.002364099).
• BP6: Variant 11-1255193-G-C is Benign according to our data. Variant chr11-1255193-G-C is described in ClinVar as Benign. ClinVar VariationId is 164005.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 = 0.0286 (3594/125626) while in subpopulation NFE AF = 0.0359 (2159/60164). AF 95% confidence interval is 0.0346. There are 63 homozygotes in GnomAd4. There are 1759 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.15817G>C	p.Ala5273Pro	missense	Exon 36 of 49	NP_002449.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.15817G>C	p.Ala5273Pro	missense	Exon 36 of 49	ENSP00000436812.1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 3595 AN: 125572 Hom.: 63 Cov.: 31

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00983

Gnomad ASJ AF: 0.0301

Gnomad EAS AF: 0.000220

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0859

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0242 AC: 3670 AN: 151624 AF XY: 0.0238

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0716

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0229

GnomAD4 exome AF: 0.0297 AC: 40417 AN: 1361426 Hom.: 763 Cov.: 35 AF XY: 0.0290 AC XY: 19517 AN XY: 671894

African (AFR) AF: 0.0116 AC: 361 AN: 31086

American (AMR) AF: 0.00600 AC: 211 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 715 AN: 24546

East Asian (EAS) AF: 0.00 AC: 0 AN: 35082

South Asian (SAS) AF: 0.00984 AC: 763 AN: 77516

European-Finnish (FIN) AF: 0.0745 AC: 3423 AN: 45948

Middle Eastern (MID) AF: 0.00461 AC: 24 AN: 5202

European-Non Finnish (NFE) AF: 0.0318 AC: 33451 AN: 1050554

Other (OTH) AF: 0.0261 AC: 1469 AN: 56316

GnomAD4 genome AF: 0.0286 AC: 3594 AN: 125626 Hom.: 63 Cov.: 31 AF XY: 0.0291 AC XY: 1759 AN XY: 60384

African (AFR) AF: 0.0156 AC: 503 AN: 32234

American (AMR) AF: 0.00982 AC: 110 AN: 11204

Ashkenazi Jewish (ASJ) AF: 0.0301 AC: 94 AN: 3120

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4524

South Asian (SAS) AF: 0.00810 AC: 33 AN: 4072

European-Finnish (FIN) AF: 0.0859 AC: 650 AN: 7566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0359 AC: 2159 AN: 60164

Other (OTH) AF: 0.0266 AC: 44 AN: 1656

Alfa AF: 0.0252 Hom.: 20

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0330 AC: 127

ExAC AF: 0.00670 AC: 704

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala5273Pro in exon 36 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 8.1% (15/186) of Finnish chromosome s from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.g ov/projects/SNP; dbSNP rs56123928).

May 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.012
DANN	Benign	0.22
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00022	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.83	N
PhyloP100		-1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.0050
Sift	Benign	0.30	T
Vest4		0.068
ClinPred		0.00054	T
GERP RS		-2.8
Varity_R		0.040
gMVP		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56123928; hg19: chr11-1276423;