11-1245486-T-C

Variant names:

• chr11-1245486-T-C
• rs80150964
• NM_002458.3:c.8606T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002458.3(MUC5B):​c.8606T>C​(p.Met2869Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2869I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1062 hom., cov: 18)
  • Exomes 𝑓: 0.10 (32064 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.43
• Publications: 7 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-AS1 (HGNC:53936): (MUC5B antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051601827).
• BP6: Variant 11-1245486-T-C is Benign according to our data. Variant chr11-1245486-T-C is described in ClinVar as Benign. ClinVar VariationId is 403148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.8606T>C	p.Met2869Thr	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-2848A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.8606T>C	p.Met2869Thr	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.57-2848A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.106 AC: 8502 AN: 79860 Hom.: 1063 Cov.: 18

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.0584

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0974

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.207 AC: 35062 AN: 169532 AF XY: 0.205

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.526

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.220

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.104 AC: 113079 AN: 1084454 Hom.: 32064 Cov.: 41 AF XY: 0.108 AC XY: 57985 AN XY: 538972

African (AFR) AF: 0.124 AC: 3086 AN: 24970

American (AMR) AF: 0.152 AC: 4865 AN: 31902

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 3411 AN: 18620

East Asian (EAS) AF: 0.531 AC: 14606 AN: 27528

South Asian (SAS) AF: 0.154 AC: 9519 AN: 61786

European-Finnish (FIN) AF: 0.162 AC: 6008 AN: 37156

Middle Eastern (MID) AF: 0.156 AC: 473 AN: 3038

European-Non Finnish (NFE) AF: 0.0775 AC: 64763 AN: 835250

Other (OTH) AF: 0.144 AC: 6348 AN: 44204

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.106 AC: 8498 AN: 79882 Hom.: 1062 Cov.: 18 AF XY: 0.101 AC XY: 3871 AN XY: 38456

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0994 AC: 2194 AN: 22064

American (AMR) AF: 0.117 AC: 886 AN: 7588

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 202 AN: 1776

East Asian (EAS) AF: 0.324 AC: 671 AN: 2068

South Asian (SAS) AF: 0.129 AC: 337 AN: 2610

European-Finnish (FIN) AF: 0.0823 AC: 427 AN: 5186

Middle Eastern (MID) AF: 0.157 AC: 28 AN: 178

European-Non Finnish (NFE) AF: 0.0974 AC: 3589 AN: 36860

Other (OTH) AF: 0.126 AC: 137 AN: 1090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.290 Hom.: 1465

ExAC AF: 0.247 AC: 28544

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.096
DANN	Benign	0.54
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00042	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.038
Sift	Benign	1.0	T
Vest4		0.0060
ClinPred		0.0013	T
GERP RS		-1.7
Varity_R		0.029
gMVP		0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs80150964; hg19: chr11-1266716; COSMIC: COSV71589827;