11-1246095-T-C

Position:

• chr11-1246095-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002458.3(MUC5B):​c.9215T>C​(p.Phe3072Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 1,603,330 control chromosomes in the GnomAD database, including 186,082 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (16471 hom., cov: 28)
  • Exomes 𝑓: 0.48 (169611 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13

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=7.070967E-6).
• BP6: Variant 11-1246095-T-C is Benign according to our data. Variant chr11-1246095-T-C is described in ClinVar as [Benign]. Clinvar id is 403150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.9215T>C	p.Phe3072Ser	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.57-3457A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.9215T>C	p.Phe3072Ser	missense_variant	31/49	5	NM_002458.3	ENSP00000436812.1
MUC5B-AS1	ENST00000532061.2	n.57-3457A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.465 AC: 68826 AN: 147874 Hom.: 16450 Cov.: 28

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.479

GnomAD3 exomes AF: 0.499 AC: 122711 AN: 245674 Hom.: 32111 AF XY: 0.493 AC XY: 65759 AN XY: 133492

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.660

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.477 AC: 694290 AN: 1455336 Hom.: 169611 Cov.: 95 AF XY: 0.475 AC XY: 343975 AN XY: 724110

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.588

Gnomad4 ASJ exome AF: 0.453

Gnomad4 EAS exome AF: 0.705

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.564

Gnomad4 NFE exome AF: 0.469

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.465 AC: 68876 AN: 147994 Hom.: 16471 Cov.: 28 AF XY: 0.473 AC XY: 34168 AN XY: 72216

Gnomad4 AFR AF: 0.361

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.663

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.484

Alfa AF: 0.466 Hom.: 6179

Bravo AF: 0.456

ESP6500AA AF: 0.205 AC: 847

ESP6500EA AF: 0.351 AC: 2932

ExAC AF: 0.489 AC: 59177

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.65
DANN	Benign	0.41
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.000080	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0000071	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.037
Sift	Benign	0.40	T
Vest4		0.027
ClinPred		0.0044	T
GERP RS		-0.50
Varity_R		0.035
gMVP		0.14

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: rs55813014; hg19: chr11-1267325; COSMIC: COSV71589890;