NM_002458.3:c.576+9G>T

Variant names:

• chr11-1227154-G-T
• rs56394097
• NM_002458.3:c.576+9G>T

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.576+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,606,824 control chromosomes in the GnomAD database, including 894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (58 hom., cov: 35)
  • Exomes 𝑓: 0.030 (836 hom.)
• Consequence: MUC5B NM_002458.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0320
• Publications: 3 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 Gene-Disease associations (from GenCC):

• interstitial lung disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-1227154-G-T is Benign according to our data. Variant chr11-1227154-G-T is described in ClinVar as Benign. ClinVar VariationId is 163994.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 = 0.023 (3501/152350) while in subpopulation NFE AF = 0.033 (2246/68018). AF 95% confidence interval is 0.0319. There are 58 homozygotes in GnomAd4. There are 1747 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 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.576+9G>T		intron	N/A	NP_002449.2	Q9HC84

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC5B	ENST00000529681.5	TSL:5 MANE Select	c.576+9G>T		intron	N/A	ENSP00000436812.1	Q9HC84
	MUC5B	ENST00000525715.5	TSL:1	n.634+9G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3501 AN: 152232 Hom.: 58 Cov.: 35

Gnomad AFR AF: 0.00559

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0262 AC: 6372 AN: 243238 AF XY: 0.0260

Gnomad AFR exome AF: 0.00617

Gnomad AMR exome AF: 0.00484

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0750

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0301 AC: 43732 AN: 1454474 Hom.: 836 Cov.: 33 AF XY: 0.0294 AC XY: 21256 AN XY: 722624

African (AFR) AF: 0.00390 AC: 130 AN: 33366

American (AMR) AF: 0.00529 AC: 235 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 758 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00988 AC: 849 AN: 85892

European-Finnish (FIN) AF: 0.0728 AC: 3782 AN: 51982

Middle Eastern (MID) AF: 0.00490 AC: 28 AN: 5710

European-Non Finnish (NFE) AF: 0.0328 AC: 36320 AN: 1107540

Other (OTH) AF: 0.0272 AC: 1630 AN: 59980

GnomAD4 genome AF: 0.0230 AC: 3501 AN: 152350 Hom.: 58 Cov.: 35 AF XY: 0.0234 AC XY: 1747 AN XY: 74500

African (AFR) AF: 0.00558 AC: 232 AN: 41590

American (AMR) AF: 0.00673 AC: 103 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4830

European-Finnish (FIN) AF: 0.0692 AC: 736 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2246 AN: 68018

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0298 Hom.: 103

Bravo AF: 0.0173

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.2
DANN	Benign	0.69
PhyloP100		0.032
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: rs56394097; hg19: chr11-1248384;