rs201778566

chr11-1250631-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002458.3(MUC5B):c.13751C>T(p.Thr4584Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 150,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.027 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00800

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036872923).
• BP6: Variant 11-1250631-C-T is Benign according to our data. Variant chr11-1250631-C-T is described in ClinVar as [Benign]. Clinvar id is 403177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0198 (2991/150794) while in subpopulation NFE AF= 0.0254 (1703/67102). AF 95% confidence interval is 0.0244. There are 1 homozygotes in gnomad4. There are 1466 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2991 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.13751C>T	p.Thr4584Ile	missense_variant	31/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.13751C>T	p.Thr4584Ile	missense_variant	31/49	5	NM_002458.3	P1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 2991 AN: 150674 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00630

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00666

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0178

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0270 AC: 39228 AN: 1453506 Hom.: 2 Cov.: 151 AF XY: 0.0263 AC XY: 19036 AN XY: 722996

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00464

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00834

Gnomad4 FIN exome AF: 0.0618

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0240

GnomAD4 genome AF: 0.0198 AC: 2991 AN: 150794 Hom.: 1 Cov.: 32 AF XY: 0.0199 AC XY: 1466 AN XY: 73656

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.00630

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00687

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.0286 Hom.: 1

ExAC AF: 0.0259 AC: 3129

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.6
Dann	Benign	0.87
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.015
Sift	Uncertain	0.024	D
Vest4		0.041
ClinPred		0.0012	T
GERP RS		-1.7
Varity_R		0.033
gMVP		0.17

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: rs201778566; hg19: chr11-1271861; COSMIC: COSV71594223; COSMIC: COSV71594223;