chr11-1247378-A-G

Position:

• chr11-1247378-A-G

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.10498A>G​(p.Ser3500Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,554,524 control chromosomes in the GnomAD database, including 380,150 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S3500R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.68 (34671 hom., cov: 25)
  • Exomes 𝑓: 0.69 (345479 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34

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=1.4510267E-6).
• BP6: Variant 11-1247378-A-G is Benign according to our data. Variant chr11-1247378-A-G is described in ClinVar as [Benign]. Clinvar id is 403162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.10498A>G	p.Ser3500Gly	missense_variant	31/49	ENST00000529681.5	NP_002449.2
MUC5B-AS1	NR_157183.1	n.56+2243T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.10498A>G	p.Ser3500Gly	missense_variant	31/49	5	NM_002458.3	ENSP00000436812	P1
MUC5B-AS1	ENST00000532061.2	n.56+2243T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.681 AC: 100556 AN: 147734 Hom.: 34644 Cov.: 25

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.676

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.683

GnomAD3 exomes AF: 0.687 AC: 161050 AN: 234520 Hom.: 58215 AF XY: 0.686 AC XY: 87473 AN XY: 127504

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.709

Gnomad ASJ exome AF: 0.698

Gnomad EAS exome AF: 0.668

Gnomad SAS exome AF: 0.660

Gnomad FIN exome AF: 0.767

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.692 AC: 972849 AN: 1406674 Hom.: 345479 Cov.: 115 AF XY: 0.690 AC XY: 483352 AN XY: 700224

Gnomad4 AFR exome AF: 0.647

Gnomad4 AMR exome AF: 0.705

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.710

Gnomad4 SAS exome AF: 0.657

Gnomad4 FIN exome AF: 0.775

Gnomad4 NFE exome AF: 0.691

Gnomad4 OTH exome AF: 0.688

GnomAD4 genome AF: 0.681 AC: 100634 AN: 147850 Hom.: 34671 Cov.: 25 AF XY: 0.685 AC XY: 49344 AN XY: 72034

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.708

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.664

Gnomad4 SAS AF: 0.641

Gnomad4 FIN AF: 0.790

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.688

Alfa AF: 0.670 Hom.: 6118

Bravo AF: 0.673

ESP6500AA AF: 0.489 AC: 2003

ESP6500EA AF: 0.575 AC: 4798

ExAC AF: 0.665 AC: 80346

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

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	0.050
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.27
DANN	Benign	0.34
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00065	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.010
Sift	Benign	0.30	T
Vest4		0.010
ClinPred		0.0030	T
GERP RS		-4.6
Varity_R		0.031
gMVP		0.25

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: rs2943527; hg19: chr11-1268608; COSMIC: COSV71589892;