11-1247407-G-T

Variant names:

• chr11-1247407-G-T
• rs2943525
• NM_002458.3:c.10527G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002458.3(MUC5B):​c.10527G>T​(p.Leu3509Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,562,312 control chromosomes in the GnomAD database, including 16,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1613 hom., cov: 26)
  • Exomes 𝑓: 0.13 (15163 hom.)
• Consequence: MUC5B NM_002458.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00600
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-1247407-G-T is Benign according to our data. Variant chr11-1247407-G-T is described in ClinVar as Benign. ClinVar VariationId is 403163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.10527G>T	p.Leu3509Leu	synonymous_variant	Exon 31 of 49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+2214C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.10527G>T	p.Leu3509Leu	synonymous_variant	Exon 31 of 49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+2214C>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 19926 AN: 134526 Hom.: 1613 Cov.: 26

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.153 AC: 36218 AN: 237222 AF XY: 0.148

Gnomad AFR exome AF: 0.0926

Gnomad AMR exome AF: 0.284

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.0521

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.133 AC: 190203 AN: 1427686 Hom.: 15163 Cov.: 117 AF XY: 0.134 AC XY: 94993 AN XY: 710692

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

African (AFR) AF: 0.0928 AC: 3068 AN: 33048

American (AMR) AF: 0.275 AC: 12158 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3402 AN: 25800

East Asian (EAS) AF: 0.107 AC: 4100 AN: 38464

South Asian (SAS) AF: 0.144 AC: 12360 AN: 85604

European-Finnish (FIN) AF: 0.222 AC: 11251 AN: 50590

Middle Eastern (MID) AF: 0.147 AC: 602 AN: 4102

European-Non Finnish (NFE) AF: 0.125 AC: 135771 AN: 1086688

Other (OTH) AF: 0.127 AC: 7491 AN: 59148

⚠️ 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: 0.148 AC: 19931 AN: 134626 Hom.: 1613 Cov.: 26 AF XY: 0.156 AC XY: 10201 AN XY: 65486

African (AFR) AF: 0.108 AC: 4010 AN: 37052

American (AMR) AF: 0.228 AC: 3108 AN: 13650

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 463 AN: 3078

East Asian (EAS) AF: 0.0693 AC: 297 AN: 4288

South Asian (SAS) AF: 0.159 AC: 659 AN: 4156

European-Finnish (FIN) AF: 0.253 AC: 2345 AN: 9264

Middle Eastern (MID) AF: 0.132 AC: 37 AN: 280

European-Non Finnish (NFE) AF: 0.143 AC: 8589 AN: 60222

Other (OTH) AF: 0.143 AC: 263 AN: 1844

Alfa AF: 0.0970 Hom.: 213

Bravo AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.56
PhyloP100		0.0060
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: rs2943525; hg19: chr11-1268637; COSMIC: COSV71593867;