11-1246497-T-C

Position:

• chr11-1246497-T-C

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.9617T>C​(p.Ile3206Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,602,608 control chromosomes in the GnomAD database, including 962 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 0.026 (69 hom., cov: 32)
  • Exomes 𝑓: 0.028 (893 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.907

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043921173).
• BP6: Variant 11-1246497-T-C is Benign according to our data. Variant chr11-1246497-T-C is described in ClinVar as [Benign]. Clinvar id is 403156.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 = 0.0257 (3763/146368) while in subpopulation NFE AF= 0.0333 (2201/66084). AF 95% confidence interval is 0.0321. There are 69 homozygotes in gnomad4. There are 1868 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3763 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.9617T>C	p.Ile3206Thr	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+3124A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.9617T>C	p.Ile3206Thr	missense_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+3124A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3764 AN: 146234 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00780

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.000421

Gnomad SAS AF: 0.00799

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0228

GnomAD3 exomes AF: 0.00969 AC: 2336 AN: 240968 Hom.: 112 AF XY: 0.00901 AC XY: 1177 AN XY: 130582

Gnomad AFR exome AF: 0.00772

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0277 AC: 40384 AN: 1456240 Hom.: 893 Cov.: 127 AF XY: 0.0272 AC XY: 19730 AN XY: 724588

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00905

Gnomad4 FIN exome AF: 0.0708

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0257 AC: 3763 AN: 146368 Hom.: 69 Cov.: 32 AF XY: 0.0261 AC XY: 1868 AN XY: 71490

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.00779

Gnomad4 ASJ AF: 0.0295

Gnomad4 EAS AF: 0.000421

Gnomad4 SAS AF: 0.00800

Gnomad4 FIN AF: 0.0708

Gnomad4 NFE AF: 0.0333

Gnomad4 OTH AF: 0.0225

Alfa AF: 0.0275 Hom.: 55

Bravo AF: 0.0199

ExAC AF: 0.0227 AC: 2749

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	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.18
DANN	Benign	0.46
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00032	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.3	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.73	N
REVEL	Benign	0.0050
Sift	Benign	1.0	T
Vest4		0.0060
ClinPred		0.0014	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.089

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: rs202001610; hg19: chr11-1267727; COSMIC: COSV71590696;