rs200811033

Positions:

• chr11-1245780-A-G

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.8900A>G​(p.Asn2967Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,612,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (0 hom., cov: 28)
  • Exomes 𝑓: 0.030 (0 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020525157).
• BP6: Variant 11-1245780-A-G is Benign according to our data. Variant chr11-1245780-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 403184.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0245 (3710/151184) while in subpopulation NFE AF= 0.0323 (2188/67844). AF 95% confidence interval is 0.0311. There are 0 homozygotes in gnomad4. There are 1853 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.8900A>G	p.Asn2967Ser	missense_variant	31/49	ENST00000529681.5
MUC5B-AS1	NR_157183.1	n.57-3142T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.8900A>G	p.Asn2967Ser	missense_variant	31/49	5	NM_002458.3	P1
MUC5B-AS1	ENST00000532061.2	n.57-3142T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3711 AN: 151066 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00750

Gnomad ASJ AF: 0.0278

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00815

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0322

Gnomad OTH AF: 0.0226

GnomAD3 exomes AF: 0.0261 AC: 6489 AN: 248850 Hom.: 0 AF XY: 0.0258 AC XY: 3488 AN XY: 135078

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00925

Gnomad FIN exome AF: 0.0720

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0296 AC: 43214 AN: 1461270 Hom.: 0 Cov.: 55 AF XY: 0.0290 AC XY: 21050 AN XY: 726916

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00933

Gnomad4 FIN exome AF: 0.0702

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0245 AC: 3710 AN: 151184 Hom.: 0 Cov.: 28 AF XY: 0.0251 AC XY: 1853 AN XY: 73872

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00749

Gnomad4 ASJ AF: 0.0278

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00816

Gnomad4 FIN AF: 0.0681

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0277 Hom.: 0

ESP6500AA AF: 0.0105 AC: 41

ESP6500EA AF: 0.0311 AC: 256

ExAC AF: 0.0273 AC: 3297

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely 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	0.098
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.7
DANN	Benign	0.80
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.020
Sift	Benign	0.44	T
Vest4		0.068
ClinPred		0.0014	T
GERP RS		0.66
Varity_R		0.030
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200811033; hg19: chr11-1267010; COSMIC: COSV71594260;