11-1242527-A-G

Position:

• chr11-1242527-A-G

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.5647A>G​(p.Ser1883Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,613,698 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 32)
  • Exomes 𝑓: 0.030 (850 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.80

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002051562).
• BP6: Variant 11-1242527-A-G is Benign according to our data. Variant chr11-1242527-A-G is described in ClinVar as [Benign]. Clinvar id is 403130.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 = 0.0251 (3823/152086) while in subpopulation NFE AF= 0.0327 (2221/67964). AF 95% confidence interval is 0.0315. There are 63 homozygotes in gnomad4. There are 1898 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3823 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.5647A>G	p.Ser1883Gly	missense_variant	31/49	ENST00000529681.5
MUC5B-AS1	NR_157183.1	n.168T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.5647A>G	p.Ser1883Gly	missense_variant	31/49	5	NM_002458.3	P1
MUC5B-AS1	ENST00000532061.2	n.168T>C		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3822 AN: 151968 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0268 AC: 6680 AN: 249352 Hom.: 144 AF XY: 0.0266 AC XY: 3592 AN XY: 135206

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00944

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0302 AC: 44149 AN: 1461612 Hom.: 850 Cov.: 81 AF XY: 0.0295 AC XY: 21483 AN XY: 727088

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00953

Gnomad4 FIN exome AF: 0.0728

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0251 AC: 3823 AN: 152086 Hom.: 63 Cov.: 32 AF XY: 0.0255 AC XY: 1898 AN XY: 74340

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0289 Hom.: 105

Bravo AF: 0.0200

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.0162 AC: 71

ESP6500EA AF: 0.0328 AC: 281

ExAC AF: 0.0279 AC: 3385

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0265

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.80
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.037	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.0090
Sift	Benign	0.18	T
Vest4		0.036
ClinPred		0.0017	T
GERP RS		-0.31
Varity_R		0.052
gMVP		0.63

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: rs78692183; hg19: chr11-1263757;