rs201822010

chr11-1249461-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002458.3(MUC5B):c.12581G>C(p.Ser4194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,611,462 control chromosomes in the GnomAD database, including 4 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.74

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008719116).
• BS2: High AC in GnomAd at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.12581G>C	p.Ser4194Thr	missense_variant	31/49	ENST00000529681.5
MUC5B-AS1	NR_157183.1	n.56+160C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.12581G>C	p.Ser4194Thr	missense_variant	31/49	5	NM_002458.3	P1
MUC5B-AS1	ENST00000532061.2	n.56+160C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000731 AC: 178 AN: 243594 Hom.: 1 AF XY: 0.000676 AC XY: 90 AN XY: 133206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.000571

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.00122 AC: 1781 AN: 1459244 Hom.: 4 Cov.: 110 AF XY: 0.00118 AC XY: 853 AN XY: 725906

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000395

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.000931

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74422

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000895

ESP6500AA AF: 0.000265 AC: 1

ESP6500EA AF: 0.00172 AC: 14

ExAC AF: 0.000640 AC: 77

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2022	The c.12581G>C (p.S4194T) alteration is located in exon 31 (coding exon 31) of the MUC5B gene. This alteration results from a G to C substitution at nucleotide position 12581, causing the serine (S) at amino acid position 4194 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, 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: Gene has no clear association with PCD, should be removed from gene list. - OB: One variant in the promoter region has been associated with risk for pulmonary fibrosis. The significance of missense variants is unclear. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.081
Dann	Benign	0.60
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.055
Sift	Uncertain	0.012	D
Vest4		0.093
MVP		0.043
ClinPred		0.031	T
GERP RS		-0.35
Varity_R		0.072
gMVP		0.54

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: rs201822010; hg19: chr11-1270691;