11-1250804-A-G

Position:

• chr11-1250804-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.13924A>G​(p.Ile4642Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,443,452 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.83

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040473044).
• BP6: Variant 11-1250804-A-G is Benign according to our data. Variant chr11-1250804-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 403193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0237 (34256/1443452) while in subpopulation NFE AF= 0.0268 (29463/1099378). AF 95% confidence interval is 0.0265. There are 1 homozygotes in gnomad4_exome. There are 16574 alleles in male gnomad4_exome subpopulation. Median coverage is 155. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 34256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.13924A>G	p.Ile4642Val	missense_variant	31/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.13924A>G	p.Ile4642Val	missense_variant	31/49	5	NM_002458.3	ENSP00000436812	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1260 AN: 147756 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00232

Gnomad ASJ AF: 0.00626

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00210

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00956

Gnomad OTH AF: 0.00689

GnomAD4 exome AF: 0.0237 AC: 34256 AN: 1443452 Hom.: 1 Cov.: 155 AF XY: 0.0231 AC XY: 16574 AN XY: 717992

Gnomad4 AFR exome AF: 0.00987

Gnomad4 AMR exome AF: 0.00377

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00643

Gnomad4 FIN exome AF: 0.0424

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00852 AC: 1260 AN: 147878 Hom.: 0 Cov.: 32 AF XY: 0.00864 AC XY: 624 AN XY: 72222

Gnomad4 AFR AF: 0.00704

Gnomad4 AMR AF: 0.00231

Gnomad4 ASJ AF: 0.00626

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.00957

Gnomad4 OTH AF: 0.00682

Alfa AF: 0.0162 Hom.: 3

ESP6500AA AF: 0.0101 AC: 43

ESP6500EA AF: 0.0198 AC: 167

ExAC AF: 0.0236 AC: 2853

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely 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: Frequency -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.017
DANN	Benign	0.68
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.020
Sift	Benign	0.57	T
Vest4		0.059
ClinPred		0.0049	T
GERP RS		-3.1
Varity_R		0.019
gMVP		0.091

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: rs188444809; hg19: chr11-1272034;