11-1246483-C-G

Position:

• chr11-1246483-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002458.3(MUC5B):​c.9603C>G​(p.Thr3201Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,608,844 control chromosomes in the GnomAD database, including 967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (73 hom., cov: 32)
  • Exomes 𝑓: 0.028 (894 hom.)
• Consequence: MUC5B NM_002458.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 11-1246483-C-G is Benign according to our data. Variant chr11-1246483-C-G is described in ClinVar as [Benign]. Clinvar id is 403155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0249 (3785/152024) while in subpopulation NFE AF= 0.0326 (2214/67932). AF 95% confidence interval is 0.0315. There are 73 homozygotes in gnomad4. There are 1878 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3785 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.9603C>G	p.Thr3201Thr	synonymous_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+3138G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.9603C>G	p.Thr3201Thr	synonymous_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+3138G>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3786 AN: 151906 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0292

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00791

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0222 AC: 5489 AN: 246832 Hom.: 136 AF XY: 0.0223 AC XY: 2988 AN XY: 134002

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.00430

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00809

Gnomad FIN exome AF: 0.0652

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0278 AC: 40542 AN: 1456820 Hom.: 894 Cov.: 127 AF XY: 0.0273 AC XY: 19809 AN XY: 724856

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00913

Gnomad4 FIN exome AF: 0.0712

Gnomad4 NFE exome AF: 0.0298

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0249 AC: 3785 AN: 152024 Hom.: 73 Cov.: 32 AF XY: 0.0253 AC XY: 1878 AN XY: 74284

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.0292

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00792

Gnomad4 FIN AF: 0.0688

Gnomad4 NFE AF: 0.0326

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0307 Hom.: 18

Bravo AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.13
DANN	Benign	0.41

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: rs201457576; hg19: chr11-1267713; COSMIC: COSV71594264;