11-1250091-C-G

Variant names:

• chr11-1250091-C-G
• rs2943517
• NM_002458.3:c.13211C>G

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.13211C>G​(p.Ala4404Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,610,152 control chromosomes in the GnomAD database, including 159,555 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (13744 hom., cov: 30)
  • Exomes 𝑓: 0.44 (145811 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.209

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=1.7681718E-4).
• BP6: Variant 11-1250091-C-G is Benign according to our data. Variant chr11-1250091-C-G is described in ClinVar as [Benign]. Clinvar id is 403174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.13211C>G	p.Ala4404Gly	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.13211C>G	p.Ala4404Gly	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 63651 AN: 150322 Hom.: 13728 Cov.: 30

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.440

GnomAD3 exomes AF: 0.469 AC: 115850 AN: 246994 Hom.: 27874 AF XY: 0.463 AC XY: 62189 AN XY: 134374

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.624

Gnomad SAS exome AF: 0.418

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.443

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.445 AC: 648945 AN: 1459718 Hom.: 145811 Cov.: 117 AF XY: 0.443 AC XY: 321912 AN XY: 726116

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.582

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.677

Gnomad4 SAS exome AF: 0.421

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.436

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.423 AC: 63691 AN: 150434 Hom.: 13744 Cov.: 30 AF XY: 0.431 AC XY: 31663 AN XY: 73416

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.534

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.445

Alfa AF: 0.429 Hom.: 3488

ExAC AF: 0.458 AC: 55204

EpiCase AF: 0.438

EpiControl AF: 0.437

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.5
DANN	Benign	0.64
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.037
Sift	Benign	0.41	T
Vest4		0.018
ClinPred		0.012	T
GERP RS		-0.67
Varity_R		0.027
gMVP		0.19

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: rs2943517; hg19: chr11-1271321; COSMIC: COSV71589898; COSMIC: COSV71589898;