rs2943531

Variant names:

• chr11-1246730-A-G
• rs2943531
• NM_002458.3:c.9850A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-1246730-A-G
• chr11-1246730-A-C
• chr11-1246730-A-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.9850A>G​(p.Thr3284Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,591,676 control chromosomes in the GnomAD database, including 475,772 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50348 hom., cov: 26)
  • Exomes 𝑓: 0.76 (425424 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.681
• Publications: 17 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=3.6329866E-6).
• BP6: Variant 11-1246730-A-G is Benign according to our data. Variant chr11-1246730-A-G is described in ClinVar as Benign. ClinVar VariationId is 403159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002458.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	NM_002458.3	MANE Select	c.9850A>G	p.Thr3284Ala	missense	Exon 31 of 49	NP_002449.2	Q9HC84
	MUC5B-AS1	NR_157183.1		n.56+2891T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.9850A>G	p.Thr3284Ala	missense	Exon 31 of 49	ENSP00000436812.1	Q9HC84
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.56+2891T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.814 AC: 120626 AN: 148106 Hom.: 50278 Cov.: 26

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.980

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.818

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.802

GnomAD2 exomes AF: 0.832 AC: 180423 AN: 216836 AF XY: 0.829

Gnomad AFR exome AF: 0.947

Gnomad AMR exome AF: 0.908

Gnomad ASJ exome AF: 0.833

Gnomad EAS exome AF: 0.987

Gnomad FIN exome AF: 0.808

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.756 AC: 1090819 AN: 1443444 Hom.: 425424 Cov.: 128 AF XY: 0.757 AC XY: 543324 AN XY: 717790

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

African (AFR) AF: 0.936 AC: 31283 AN: 33424

American (AMR) AF: 0.885 AC: 39424 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 20229 AN: 25742

East Asian (EAS) AF: 0.978 AC: 38795 AN: 39662

South Asian (SAS) AF: 0.834 AC: 71404 AN: 85574

European-Finnish (FIN) AF: 0.767 AC: 40535 AN: 52848

Middle Eastern (MID) AF: 0.804 AC: 4459 AN: 5544

European-Non Finnish (NFE) AF: 0.728 AC: 797885 AN: 1096434

Other (OTH) AF: 0.784 AC: 46805 AN: 59678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.815 AC: 120759 AN: 148232 Hom.: 50348 Cov.: 26 AF XY: 0.820 AC XY: 59205 AN XY: 72226

African (AFR) AF: 0.934 AC: 37857 AN: 40548

American (AMR) AF: 0.849 AC: 12826 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2647 AN: 3390

East Asian (EAS) AF: 0.980 AC: 4850 AN: 4948

South Asian (SAS) AF: 0.829 AC: 3857 AN: 4652

European-Finnish (FIN) AF: 0.790 AC: 7833 AN: 9916

Middle Eastern (MID) AF: 0.806 AC: 232 AN: 288

European-Non Finnish (NFE) AF: 0.727 AC: 48276 AN: 66428

Other (OTH) AF: 0.805 AC: 1655 AN: 2056

Alfa AF: 0.760 Hom.: 8271

Bravo AF: 0.826

ESP6500AA AF: 0.874 AC: 3386

ESP6500EA AF: 0.580 AC: 4783

ExAC AF: 0.774 AC: 93199

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.30
DEOGEN2	Benign	0.021	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000036	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.68
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Vest4		0.021
ClinPred		0.00028	T
GERP RS		-4.4
Varity_R		0.017
gMVP		0.15
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: rs2943531; hg19: chr11-1267960; COSMIC: COSV71589891;