11-1248477-C-T

Variant names:

• chr11-1248477-C-T
• rs187569173
• NM_002458.3:c.11597C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.11597C>T​(p.Pro3866Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 1,568,910 control chromosomes in the GnomAD database, including 6,121 homozygotes. 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. P3866T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (354 hom., cov: 29)
  • Exomes 𝑓: 0.056 (5767 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.43
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021577775).
• BP6: Variant 11-1248477-C-T is Benign according to our data. Variant chr11-1248477-C-T is described in ClinVar as Benign. ClinVar VariationId is 403170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.11597C>T	p.Pro3866Leu	missense_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+1144G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.11597C>T	p.Pro3866Leu	missense_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+1144G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0506 AC: 7384 AN: 145934 Hom.: 354 Cov.: 29

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0752

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0486

GnomAD2 exomes AF: 0.0576 AC: 14017 AN: 243446 AF XY: 0.0538

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.0412

Gnomad EAS exome AF: 0.00156

Gnomad FIN exome AF: 0.0868

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0562 AC: 79967 AN: 1422858 Hom.: 5767 Cov.: 153 AF XY: 0.0558 AC XY: 39526 AN XY: 708412

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

African (AFR) AF: 0.0156 AC: 518 AN: 33118

American (AMR) AF: 0.140 AC: 6132 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 1024 AN: 25338

East Asian (EAS) AF: 0.00176 AC: 70 AN: 39692

South Asian (SAS) AF: 0.0519 AC: 4416 AN: 85132

European-Finnish (FIN) AF: 0.0972 AC: 4823 AN: 49622

Middle Eastern (MID) AF: 0.0346 AC: 195 AN: 5642

European-Non Finnish (NFE) AF: 0.0553 AC: 59801 AN: 1081662

Other (OTH) AF: 0.0509 AC: 2988 AN: 58720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0506 AC: 7388 AN: 146052 Hom.: 354 Cov.: 29 AF XY: 0.0536 AC XY: 3815 AN XY: 71240

African (AFR) AF: 0.0165 AC: 669 AN: 40550

American (AMR) AF: 0.103 AC: 1547 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 131 AN: 3318

East Asian (EAS) AF: 0.00194 AC: 10 AN: 5148

South Asian (SAS) AF: 0.0484 AC: 228 AN: 4710

European-Finnish (FIN) AF: 0.105 AC: 982 AN: 9390

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0564 AC: 3650 AN: 64704

Other (OTH) AF: 0.0480 AC: 98 AN: 2040

Alfa AF: 0.0462 Hom.: 123

ESP6500AA AF: 0.0101 AC: 42

ESP6500EA AF: 0.0408 AC: 343

ExAC AF: 0.0566 AC: 6845

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	0.054
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.017
DANN	Benign	0.50
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.023
Sift	Benign	0.23	T
Vest4		0.019
ClinPred		0.0025	T
GERP RS		0.12
Varity_R		0.022
gMVP		0.32
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: rs187569173; hg19: chr11-1269707; COSMIC: COSV71595112;