rs55657020

chr11-1257566-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002458.3(MUC5B):c.16306G>A(p.Val5436Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,607,968 control chromosomes in the GnomAD database, including 884 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (57 hom., cov: 32)
  • Exomes 𝑓: 0.030 (827 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00300

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031365752).
• BP6: Variant 11-1257566-G-A is Benign according to our data. Variant chr11-1257566-G-A is described in ClinVar as [Benign]. Clinvar id is 164009.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-1257566-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0228 (3479/152290) while in subpopulation NFE AF= 0.0328 (2228/68016). AF 95% confidence interval is 0.0316. There are 57 homozygotes in gnomad4. There are 1737 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3479 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.16306G>A	p.Val5436Met	missense_variant	41/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.16306G>A	p.Val5436Met	missense_variant	41/49	5	NM_002458.3	P1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3479 AN: 152172 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0254 AC: 6197 AN: 243876 Hom.: 126 AF XY: 0.0254 AC XY: 3382 AN XY: 133286

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.00485

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00942

Gnomad FIN exome AF: 0.0740

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0298 AC: 43348 AN: 1455678 Hom.: 827 Cov.: 33 AF XY: 0.0292 AC XY: 21121 AN XY: 724348

Gnomad4 AFR exome AF: 0.00391

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00952

Gnomad4 FIN exome AF: 0.0718

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0270

GnomAD4 genome AF: 0.0228 AC: 3479 AN: 152290 Hom.: 57 Cov.: 32 AF XY: 0.0233 AC XY: 1737 AN XY: 74454

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.0690

Gnomad4 NFE AF: 0.0328

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0294 Hom.: 78

Bravo AF: 0.0172

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00746 AC: 32

ESP6500EA AF: 0.0317 AC: 269

ExAC AF: 0.0270 AC: 3256

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0264

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Val5436Met in exon 41 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 3.2% (269/8482) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs55657020). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	17
Dann	Benign	0.65
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.037
Sift	Benign	0.12	T
Vest4		0.10
ClinPred		0.0092	T
GERP RS		0.71
Varity_R		0.042
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55657020; hg19: chr11-1278796;