rs56293203

Positions:

• chr11-1226857-G-A

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.442G>A​(p.Val148Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,607,016 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0099 (93 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.180

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 (MetaRNN=0.0045601726).
• BP6: Variant 11-1226857-G-A is Benign according to our data. Variant chr11-1226857-G-A is described in ClinVar as [Benign]. Clinvar id is 163993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00993 (14444/1454958) while in subpopulation MID AF= 0.0248 (143/5766). AF 95% confidence interval is 0.0215. There are 93 homozygotes in gnomad4_exome. There are 7373 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1275 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.442G>A	p.Val148Ile	missense_variant	4/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.442G>A	p.Val148Ile	missense_variant	4/49	5	NM_002458.3	ENSP00000436812	P1
MUC5B	ENST00000525715.5	n.500G>A		non_coding_transcript_exon_variant	4/26	1

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1274 AN: 151940 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00924 AC: 2206 AN: 238700 Hom.: 17 AF XY: 0.00943 AC XY: 1236 AN XY: 131058

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.00624

Gnomad ASJ exome AF: 0.00703

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00808

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00986

GnomAD4 exome AF: 0.00993 AC: 14444 AN: 1454958 Hom.: 93 Cov.: 35 AF XY: 0.0102 AC XY: 7373 AN XY: 724028

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.00793

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00752

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00849

GnomAD4 genome AF: 0.00838 AC: 1275 AN: 152058 Hom.: 6 Cov.: 34 AF XY: 0.00844 AC XY: 627 AN XY: 74330

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00665

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0104 Hom.: 4

Bravo AF: 0.00687

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00173 AC: 7

ESP6500EA AF: 0.00997 AC: 83

ExAC AF: 0.00965 AC: 1163

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00998

EpiControl AF: 0.0113

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

May 11, 2015

p.Val148Ile in exon 4 of MUC5B: This variant is not expected to have clinical si gnificance because it has been identified in 1.2% (795/61246) of European chromo somes, including 6 homozygotes, by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs56293203). -

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	0.067
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.8
DANN	Benign	0.58
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.16
Sift	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.12
ClinPred		0.0024	T
GERP RS		-3.7
Varity_R		0.046
gMVP		0.58

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: rs56293203; hg19: chr11-1248087;