rs201530874

Positions:

• chr11-1254776-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002458.3(MUC5B):​c.15560G>A​(p.Arg5187His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,612,882 control chromosomes in the GnomAD database, including 20 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 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (20 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.36

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056170225).
• BP6: Variant 11-1254776-G-A is Benign according to our data. Variant chr11-1254776-G-A is described in ClinVar as [Benign]. Clinvar id is 504736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.15560G>A	p.Arg5187His	missense_variant	35/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.15560G>A	p.Arg5187His	missense_variant	35/49	5	NM_002458.3	ENSP00000436812.1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00291 AC: 720 AN: 247842 Hom.: 4 AF XY: 0.00346 AC XY: 467 AN XY: 135012

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00860

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00515

GnomAD4 exome AF: 0.00196 AC: 2864 AN: 1460556 Hom.: 20 Cov.: 34 AF XY: 0.00229 AC XY: 1665 AN XY: 726550

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00850

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74484

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00249 Hom.: 5

Bravo AF: 0.00183

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00176 AC: 15

ExAC AF: 0.00273 AC: 330

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00385

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	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2017

p.Arg5187His in exon 35 of MUC5B: This variant is not expected to have clinical significance because it has been identified in 0.9% (264/30774) of South Asian c hromosomes and 1.6% (159/10110) of Ashkenazi Jewish chromosomes, including 4 hom ozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs201530874). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.3
DANN	Benign	0.59
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.95	L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.088
Sift	Benign	0.55	T
Vest4		0.26
MVP		0.23
ClinPred		0.011	T
GERP RS		0.68
Varity_R		0.031
gMVP		0.50

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: rs201530874; hg19: chr11-1276006; COSMIC: COSV71591097; COSMIC: COSV71591097;