11-1244556-C-T

Position:

• chr11-1244556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.7676C>T​(p.Thr2559Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,601,592 control chromosomes in the GnomAD database, including 69,187 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (12953 hom., cov: 25)
  • Exomes 𝑓: 0.38 (56234 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.90

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.851046E-5).
• BP6: Variant 11-1244556-C-T is Benign according to our data. Variant chr11-1244556-C-T is described in ClinVar as [Benign]. Clinvar id is 403143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.7676C>T	p.Thr2559Met	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-1918G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.7676C>T	p.Thr2559Met	missense_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.57-1918G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.417 AC: 61068 AN: 146584 Hom.: 12938 Cov.: 25

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.446 AC: 106515 AN: 238782 Hom.: 22221 AF XY: 0.441 AC XY: 57422 AN XY: 130350

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.630

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.382 AC: 555675 AN: 1454898 Hom.: 56234 Cov.: 107 AF XY: 0.383 AC XY: 276877 AN XY: 723846

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.385

Gnomad4 EAS exome AF: 0.659

Gnomad4 SAS exome AF: 0.386

Gnomad4 FIN exome AF: 0.459

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.391

GnomAD4 genome AF: 0.417 AC: 61108 AN: 146694 Hom.: 12953 Cov.: 25 AF XY: 0.423 AC XY: 30222 AN XY: 71366

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.427

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.502

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.431

Alfa AF: 0.333 Hom.: 1293

ExAC AF: 0.430 AC: 51773

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified Benign:1

Benign, 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 associated with pulmonary fibrosis -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.2
DANN	Benign	0.50
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.000029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.085
Sift	Uncertain	0.0040	D
Vest4		0.015
ClinPred		0.010	T
GERP RS		-3.8
Varity_R		0.017
gMVP		0.21

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: rs60787297; hg19: chr11-1265786; COSMIC: COSV71589896;