11-1255097-G-A

Position:

• chr11-1255097-G-A

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.15721G>A​(p.Ala5241Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,592,076 control chromosomes in the GnomAD database, including 2,941 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (467 hom., cov: 33)
  • Exomes 𝑓: 0.020 (2474 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.58

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034210384).
• BP6: Variant 11-1255097-G-A is Benign according to our data. Variant chr11-1255097-G-A is described in ClinVar as [Benign]. Clinvar id is 226734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.15721G>A	p.Ala5241Thr	missense_variant	36/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.15721G>A	p.Ala5241Thr	missense_variant	36/49	5	NM_002458.3	ENSP00000436812	P1

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6760 AN: 152134 Hom.: 468 Cov.: 33

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0625 AC: 13152 AN: 210310 Hom.: 1212 AF XY: 0.0586 AC XY: 6699 AN XY: 114226

Gnomad AFR exome AF: 0.0872

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.00236

Gnomad EAS exome AF: 0.281

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.00270

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0203 AC: 29223 AN: 1439824 Hom.: 2474 Cov.: 36 AF XY: 0.0220 AC XY: 15718 AN XY: 714222

Gnomad4 AFR exome AF: 0.0795

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.00179

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.000598

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.0445 AC: 6777 AN: 152252 Hom.: 467 Cov.: 33 AF XY: 0.0484 AC XY: 3602 AN XY: 74438

Gnomad4 AFR AF: 0.0820

Gnomad4 AMR AF: 0.0755

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.0422

Alfa AF: 0.0158 Hom.: 247

Bravo AF: 0.0522

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0770 AC: 322

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.0544 AC: 6487

Asia WGS AF: 0.162 AC: 565 AN: 3478

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	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Ala5241Thr in exon 36 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 7.7% (322/4182) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs3829224). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.9
DANN	Benign	0.42
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.32	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.054
Sift	Benign	0.29	T
Vest4		0.018
ClinPred		0.00018	T
GERP RS		-8.4
Varity_R		0.035
gMVP		0.23

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: rs3829224; hg19: chr11-1276327; COSMIC: COSV71594410; COSMIC: COSV71594410;