chr11-1257533-G-C

Variant names:

• chr11-1257533-G-C
• rs201746407
• NM_002458.3:c.16273G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002458.3(MUC5B):​c.16273G>C​(p.Gly5425Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,868 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• interstitial lung disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.16273G>C	p.Gly5425Arg	missense_variant	Exon 41 of 49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.16273G>C	p.Gly5425Arg	missense_variant	Exon 41 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000526859.1	c.-93G>C		upstream_gene_variant		3		ENSP00000434539.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724348

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111408

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.59
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.0
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	D
Vest4		0.40
MVP		0.33
ClinPred		0.56	D
GERP RS		4.0
PromoterAI		-0.0023	Neutral
Varity_R		0.22
gMVP		0.90
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs201746407; hg19: chr11-1278763;