chr11-1226207-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002458.3(MUC5B):c.130G>A(p.Ala44Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

MUC5B
NM_002458.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.520

Publications

1 publications found

Variant links:

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

MUC5B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047291607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3 link	c.130G>A	p.Ala44Thr	missense_variant, splice_region_variant	Exon 3 of 49	ENST00000529681.5	NP_002449.2	Q9HC84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5 link	c.130G>A	p.Ala44Thr	missense_variant, splice_region_variant	Exon 3 of 49	5	NM_002458.3	ENSP00000436812.1		Q9HC84
MUC5B	ENST00000525715.5 link	n.188G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 26	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000636

AC:

AN:

157274

AF XY:

0.0000119

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000358

AC:

AN:

1398246

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31666

American (AMR)

AF:

0.00

AC:

AN:

36210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25204

East Asian (EAS)

AF:

0.00

AC:

AN:

35812

South Asian (SAS)

AF:

0.00

AC:

AN:

79316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1080716

Other (OTH)

AF:

0.0000172

AC:

AN:

58060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.130G>A (p.A44T) alteration is located in exon 3 (coding exon 3) of the MUC5B gene. This alteration results from a G to A substitution at nucleotide position 130, causing the alanine (A) at amino acid position 44 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.50

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.018

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.42

M_CAP

Benign

0.0022

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.52

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.90

REVEL

Benign

0.035

Sift

Benign

0.39

Polyphen

0.0040

Vest4

0.068

MutPred

0.20

Gain of glycosylation at A44 (P = 0.0073);

MVP

0.068

ClinPred

0.033

GERP RS

-4.9

Varity_R

0.023

gMVP

0.59

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr11-1226207-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over