NM_002458.3:c.9010G>A

Variant names:

• chr11-1245890-G-A
• rs116870693
• NM_002458.3:c.9010G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.9010G>A​(p.Ala3004Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,612,868 control chromosomes in the GnomAD database, including 287 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (10 hom., cov: 29)
  • Exomes 𝑓: 0.030 (277 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.876
• 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=0.0030438304).
• BP6: Variant 11-1245890-G-A is Benign according to our data. Variant chr11-1245890-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 403185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0247 (3739/151410) while in subpopulation NFE AF = 0.0324 (2203/67902). AF 95% confidence interval is 0.0313. There are 10 homozygotes in GnomAd4. There are 1860 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.9010G>A	p.Ala3004Thr	missense	Exon 31 of 49	NP_002449.2
	MUC5B-AS1	NR_157183.1		n.57-3252C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.9010G>A	p.Ala3004Thr	missense	Exon 31 of 49	ENSP00000436812.1
	MUC5B-AS1	ENST00000532061.2	TSL:5	n.57-3252C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3740 AN: 151290 Hom.: 10 Cov.: 29

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00742

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.00833

Gnomad FIN AF: 0.0684

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0263 AC: 6558 AN: 249208 AF XY: 0.0261

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.0340

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0298 AC: 43529 AN: 1461458 Hom.: 277 Cov.: 66 AF XY: 0.0292 AC XY: 21209 AN XY: 727038

African (AFR) AF: 0.0112 AC: 376 AN: 33434

American (AMR) AF: 0.00570 AC: 255 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 761 AN: 26122

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00955 AC: 824 AN: 86246

European-Finnish (FIN) AF: 0.0719 AC: 3837 AN: 53330

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.0322 AC: 35805 AN: 1111786

Other (OTH) AF: 0.0272 AC: 1639 AN: 60362

GnomAD4 genome AF: 0.0247 AC: 3739 AN: 151410 Hom.: 10 Cov.: 29 AF XY: 0.0251 AC XY: 1860 AN XY: 73966

African (AFR) AF: 0.0126 AC: 516 AN: 41056

American (AMR) AF: 0.00741 AC: 113 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3460

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5106

South Asian (SAS) AF: 0.00833 AC: 40 AN: 4800

European-Finnish (FIN) AF: 0.0684 AC: 721 AN: 10540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0324 AC: 2203 AN: 67902

Other (OTH) AF: 0.0214 AC: 45 AN: 2104

Alfa AF: 0.0222 Hom.: 12

ESP6500AA AF: 0.0159 AC: 68

ESP6500EA AF: 0.0334 AC: 283

ExAC AF: 0.0273 AC: 3312

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.59
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.88
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.012
Sift	Benign	0.26	T
Vest4		0.087
ClinPred		0.00013	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.026
gMVP		0.17
Mutation Taster		=100/0	polymorphism

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: rs116870693; hg19: chr11-1267120; COSMIC: COSV71593744;