rs2943521

Positions:

• chr11-1248605-G-A
• chr11-1248605-G-C

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.11725G>A​(p.Val3909Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,609,662 control chromosomes in the GnomAD database, including 163,161 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14462 hom., cov: 28)
  • Exomes 𝑓: 0.45 (148699 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.04

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=6.6728385E-6).
• BP6: Variant 11-1248605-G-A is Benign according to our data. Variant chr11-1248605-G-A is described in ClinVar as [Benign]. Clinvar id is 403171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.11725G>A	p.Val3909Ile	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+1016C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.11725G>A	p.Val3909Ile	missense_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+1016C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.431 AC: 64766 AN: 150336 Hom.: 14445 Cov.: 28

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.443

GnomAD3 exomes AF: 0.469 AC: 113204 AN: 241520 Hom.: 28153 AF XY: 0.462 AC XY: 60868 AN XY: 131616

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.590

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.660

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.491

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.446 AC: 651299 AN: 1459208 Hom.: 148699 Cov.: 139 AF XY: 0.445 AC XY: 323023 AN XY: 725890

Gnomad4 AFR exome AF: 0.318

Gnomad4 AMR exome AF: 0.581

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.705

Gnomad4 SAS exome AF: 0.425

Gnomad4 FIN exome AF: 0.490

Gnomad4 NFE exome AF: 0.436

Gnomad4 OTH exome AF: 0.442

GnomAD4 genome AF: 0.431 AC: 64807 AN: 150454 Hom.: 14462 Cov.: 28 AF XY: 0.438 AC XY: 32203 AN XY: 73478

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.537

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.658

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.507

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.449

Alfa AF: 0.430 Hom.: 2421

Bravo AF: 0.431

ExAC AF: 0.454 AC: 54754

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

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: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.75
DEOGEN2	Benign	0.015	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0000067	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-1.6	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Vest4		0.041
ClinPred		0.0074	T
GERP RS		-6.2
Varity_R		0.019
gMVP		0.13

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: rs2943521; hg19: chr11-1269835; COSMIC: COSV71589897;