11-1242953-G-A

Position:

• chr11-1242953-G-A

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.6073G>A​(p.Ala2025Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,611,204 control chromosomes in the GnomAD database, including 16,603 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 0.11 (1023 hom., cov: 31)
  • Exomes 𝑓: 0.14 (15580 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.36

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:53936): (MUC5B antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015899241).
• BP6: Variant 11-1242953-G-A is Benign according to our data. Variant chr11-1242953-G-A is described in ClinVar as [Benign]. Clinvar id is 403133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.6073G>A	p.Ala2025Thr	missense_variant	31/49	ENST00000529681.5
MUC5B-AS1	NR_157183.1	n.57-315C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.6073G>A	p.Ala2025Thr	missense_variant	31/49	5	NM_002458.3	P1
MUC5B-AS1	ENST00000532061.2	n.57-315C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16143 AN: 149706 Hom.: 1020 Cov.: 31

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.0908

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.120 AC: 29870 AN: 249148 Hom.: 2130 AF XY: 0.125 AC XY: 16919 AN XY: 135192

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.0647

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0159

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.0932

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.142 AC: 207502 AN: 1461380 Hom.: 15580 Cov.: 139 AF XY: 0.143 AC XY: 103927 AN XY: 726996

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.0667

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.0978

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.108 AC: 16145 AN: 149824 Hom.: 1023 Cov.: 31 AF XY: 0.105 AC XY: 7652 AN XY: 73094

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.0906

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0873

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.110

Alfa AF: 0.143 Hom.: 545

Bravo AF: 0.105

ESP6500AA AF: 0.0446 AC: 188

ESP6500EA AF: 0.150 AC: 1261

ExAC AF: 0.122 AC: 14797

EpiCase AF: 0.160

EpiControl AF: 0.154

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

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.048
DANN	Benign	0.34
DEOGEN2	Benign	0.015	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Vest4		0.015
ClinPred		0.000020	T
GERP RS		-1.7
Varity_R		0.018
gMVP		0.13

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: rs34739266; hg19: chr11-1264183; COSMIC: COSV71594350; COSMIC: COSV71594350;