rs371465585

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002458.3(MUC5B):c.845C>A(p.Ala282Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 in 1,534,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

MUC5B
NM_002458.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0240

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 links:

MUC5B (HGNC:):

MUC5B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08309758).

BP6

Variant 11-1228634-C-A is Benign according to our data. Variant chr11-1228634-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3 linkuse as main transcript	c.845C>A	p.Ala282Glu	missense_variant	8/49	ENST00000529681.5	NP_002449.2	Q9HC84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MUC5B	ENST00000529681.5 linkuse as main transcript	c.845C>A	p.Ala282Glu	missense_variant	8/49	5	NM_002458.3	ENSP00000436812.1	Q9HC84
MUC5B	ENST00000525715.5 linkuse as main transcript	n.903C>A		non_coding_transcript_exon_variant	8/26	1
MUC5B	ENST00000531082.1 linkuse as main transcript	n.115C>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000243

AC:

AN:

135968

Hom.:

AF XY:

0.000231

AC XY:

AN XY:

73628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000474

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000596

AC:

824

AN:

1381866

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

404

AN XY:

681948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000635

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000734

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000217

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000846

AC:

ESP6500EA

AF:

0.000139

AC:

ExAC

AF:

0.000105

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2024	The c.845C>A (p.A282E) alteration is located in exon 8 (coding exon 8) of the MUC5B gene. This alteration results from a C to A substitution at nucleotide position 845, causing the alanine (A) at amino acid position 282 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2018	The p.Ala282Glu variant in MUC5B was observed by our laboratory in the heterozyg ous state in 1 individual with pulmonary disease, but this individual also harbo red one pathogenic and one variant of uncertain significance in CFTR. This varia nt has been identified in 31/65026 European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs371465585). Alani ne (Ala) at position 282 is not conserved in mammals or evolutionarily distant s pecies and 6 species, including 2 mammals carry a glutamic acid (Glu) at this po sition, supporting that this change may be tolerated. In summary, the p.Ala282Gl u variant is likely benign based. ACMG/AMP Criteria applied: BP4, BP5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.23

DANN

Benign

0.41

DEOGEN2

Benign

0.015

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.069

M_CAP

Benign

0.035

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.43

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.45

REVEL

Benign

0.16

Sift

Benign

1.0

Polyphen

0.0

Vest4

0.070

MVP

0.21

ClinPred

0.012

GERP RS

-6.8

Varity_R

0.059

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over