11-1246473-G-C

Position:

• chr11-1246473-G-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.9593G>C​(p.Ser3198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,608,120 control chromosomes in the GnomAD database, including 966 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 (72 hom., cov: 32)
  • Exomes 𝑓: 0.028 (894 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.12

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=0.0037986338).
• BP6: Variant 11-1246473-G-C is Benign according to our data. Variant chr11-1246473-G-C is described in ClinVar as [Benign]. Clinvar id is 403154.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 (3794/151156) while in subpopulation NFE AF= 0.0327 (2216/67694). AF 95% confidence interval is 0.0316. There are 72 homozygotes in gnomad4. There are 1886 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3794 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.9593G>C	p.Ser3198Thr	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+3148C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.9593G>C	p.Ser3198Thr	missense_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.56+3148C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3795 AN: 151032 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00762

Gnomad ASJ AF: 0.0296

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00820

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0221

GnomAD3 exomes AF: 0.0246 AC: 6092 AN: 247928 Hom.: 144 AF XY: 0.0245 AC XY: 3300 AN XY: 134576

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00916

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0278 AC: 40546 AN: 1456964 Hom.: 894 Cov.: 127 AF XY: 0.0273 AC XY: 19810 AN XY: 724928

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: 0.00916

Gnomad4 FIN exome AF: 0.0712

Gnomad4 NFE exome AF: 0.0298

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0251 AC: 3794 AN: 151156 Hom.: 72 Cov.: 32 AF XY: 0.0255 AC XY: 1886 AN XY: 73852

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00761

Gnomad4 ASJ AF: 0.0296

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00821

Gnomad4 FIN AF: 0.0696

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0270 Hom.: 27

Bravo AF: 0.0199

ESP6500AA AF: 0.0144 AC: 62

ESP6500EA AF: 0.0277 AC: 236

ExAC AF: 0.0238 AC: 2885

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	0.065
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.019
DANN	Benign	0.56
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.0030
Sift	Benign	1.0	T
Vest4		0.020
ClinPred		0.00050	T
GERP RS		-4.6
Varity_R		0.034
gMVP		0.18

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: rs117501397; hg19: chr11-1267703;