rs56179538

Positions:

• chr11-1227764-G-A
• chr11-1227764-G-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.757G>A​(p.Gly253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 717,660 control chromosomes in the GnomAD database, including 248 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 (171 hom., cov: 34)
  • Exomes 𝑓: 0.0047 (77 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.75

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002224356).
• BP6: Variant 11-1227764-G-A is Benign according to our data. Variant chr11-1227764-G-A is described in ClinVar as [Benign]. Clinvar id is 178784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.757G>A	p.Gly253Ser	missense_variant	7/49	ENST00000529681.5	NP_002449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.757G>A	p.Gly253Ser	missense_variant	7/49	5	NM_002458.3	ENSP00000436812	P1
MUC5B	ENST00000525715.5	n.815G>A		non_coding_transcript_exon_variant	7/26	1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3943 AN: 152204 Hom.: 171 Cov.: 34

Gnomad AFR AF: 0.0869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00750 AC: 1158 AN: 154466 Hom.: 41 AF XY: 0.00617 AC XY: 507 AN XY: 82210

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.00540

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00807

GnomAD4 exome AF: 0.00470 AC: 2655 AN: 565338 Hom.: 77 Cov.: 0 AF XY: 0.00402 AC XY: 1225 AN XY: 305038

Gnomad4 AFR exome AF: 0.0869

Gnomad4 AMR exome AF: 0.00972

Gnomad4 ASJ exome AF: 0.00549

Gnomad4 EAS exome AF: 0.0000311

Gnomad4 SAS exome AF: 0.000924

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0259 AC: 3950 AN: 152322 Hom.: 171 Cov.: 34 AF XY: 0.0244 AC XY: 1820 AN XY: 74490

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0110 Hom.: 21

Bravo AF: 0.0300

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0701 AC: 259

ESP6500EA AF: 0.00179 AC: 14

ExAC AF: 0.00499 AC: 498

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gly253Ser in exon 7 of MUC5B: This variant is not expected to have clinical sign ificance because it has been identified in 7.0% (259/3694) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs56179538). -

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	0.062
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.029
DANN	Benign	0.70
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.63	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.020
Sift	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.043
ClinPred		0.00021	T
GERP RS		-5.1
Varity_R		0.027
gMVP		0.40

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: rs56179538; hg19: chr11-1248994;