rs371465585

chr11-1228634-C-Achr11-1228634-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A282V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0240

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]

ACMG classification

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: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.845C>A	p.Ala282Glu	missense_variant	8/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.845C>A	p.Ala282Glu	missense_variant	8/49	5	NM_002458.3	P1
MUC5B	ENST00000525715.5	n.903C>A		non_coding_transcript_exon_variant	8/26	1
MUC5B	ENST00000531082.1	n.115C>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152200 Hom.: 0 Cov.: 34

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: 33 AN: 135968 Hom.: 0 AF XY: 0.000231 AC XY: 17 AN XY: 73628

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.: 1 Cov.: 32 AF XY: 0.000592 AC XY: 404 AN XY: 681948

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: 33 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.000215 AC XY: 16 AN XY: 74354

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.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000846 AC: 3

ESP6500EA AF: 0.000139 AC: 1

ExAC AF: 0.000105 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign: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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.23
Dann	Benign	0.41
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.069	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.43	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.070
MVP		0.21
ClinPred		0.012	T
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

Other links and lift over

dbSNP: rs371465585; hg19: chr11-1249864;