rs185838223

Positions:

• chr11-1249417-G-C

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.12537G>C​(p.Gln4179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,611,248 control chromosomes in the GnomAD database, including 3,306 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (348 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2958 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.21

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-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002925545).
• BP6: Variant 11-1249417-G-C is Benign according to our data. Variant chr11-1249417-G-C is described in ClinVar as [Benign]. Clinvar id is 403172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.12537G>C	p.Gln4179His	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+204C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.12537G>C	p.Gln4179His	missense_variant	31/49	5	NM_002458.3	ENSP00000436812	P1
MUC5B-AS1	ENST00000532061.2	n.56+204C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9485 AN: 152076 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0950

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0536

GnomAD3 exomes AF: 0.0653 AC: 15984 AN: 244920 Hom.: 811 AF XY: 0.0605 AC XY: 8092 AN XY: 133826

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.00106

Gnomad SAS exome AF: 0.0485

Gnomad FIN exome AF: 0.0849

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0651

GnomAD4 exome AF: 0.0564 AC: 82339 AN: 1459054 Hom.: 2958 Cov.: 118 AF XY: 0.0558 AC XY: 40536 AN XY: 725810

Gnomad4 AFR exome AF: 0.0619

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.0376

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.0512

Gnomad4 FIN exome AF: 0.0825

Gnomad4 NFE exome AF: 0.0545

Gnomad4 OTH exome AF: 0.0522

GnomAD4 genome AF: 0.0623 AC: 9489 AN: 152194 Hom.: 348 Cov.: 32 AF XY: 0.0653 AC XY: 4861 AN XY: 74398

Gnomad4 AFR AF: 0.0634

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0503

Gnomad4 FIN AF: 0.0950

Gnomad4 NFE AF: 0.0531

Gnomad4 OTH AF: 0.0531

Alfa AF: 0.0556 Hom.: 51

Bravo AF: 0.0645

ESP6500AA AF: 0.0626 AC: 237

ESP6500EA AF: 0.0528 AC: 432

ExAC AF: 0.0598 AC: 7160

EpiCase AF: 0.0497

EpiControl AF: 0.0465

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
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

Mar 28, 2016

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 -

Interstitial lung disease 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.52
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.039	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.076
Sift	Benign	0.51	T
Vest4		0.068
ClinPred		0.0027	T
GERP RS		-7.3
Varity_R		0.067
gMVP		0.72

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: rs185838223; hg19: chr11-1270647;