11-1227154-G-T

Variant names:

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

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.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

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 (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 id is 163994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1227154-G-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.576+9G>T		intron_variant	Intron 5 of 48	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.576+9G>T		intron_variant	Intron 5 of 48	5	NM_002458.3	ENSP00000436812.1
MUC5B	ENST00000525715.5	n.634+9G>T		intron_variant	Intron 5 of 25	1

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

GnomAD3 exomes AF: 0.0262 AC: 6372 AN: 243238 Hom.: 131 AF XY: 0.0260 AC XY: 3455 AN XY: 132812

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 SAS exome AF: 0.00963

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

Gnomad4 AFR exome AF: 0.00390

Gnomad4 AMR exome AF: 0.00529

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00988

Gnomad4 FIN exome AF: 0.0728

Gnomad4 NFE exome AF: 0.0328

Gnomad4 OTH exome AF: 0.0272

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

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.0330

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0287 Hom.: 30

Bravo AF: 0.0173

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

576+9G>T in intron 5 of MUC5B: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 3.2% (268/8278) of European American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs56394097). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.2
DANN	Benign	0.69

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: rs56394097; hg19: chr11-1248384;