chr11-1246458-T-C

Position:

• chr11-1246458-T-C

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.9578T>C​(p.Leu3193Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,599,640 control chromosomes in the GnomAD database, including 968 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (74 hom., cov: 32)
  • Exomes 𝑓: 0.028 (894 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.873

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=0.002866596).
• BP6: Variant 11-1246458-T-C is Benign according to our data. Variant chr11-1246458-T-C is described in ClinVar as [Benign]. Clinvar id is 403153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0262 (3801/145264) while in subpopulation NFE AF= 0.0338 (2217/65620). AF 95% confidence interval is 0.0326. There are 74 homozygotes in gnomad4. There are 1889 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3801 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.9578T>C	p.Leu3193Pro	missense_variant	31/49	ENST00000529681.5
MUC5B-AS1	NR_157183.1	n.56+3163A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.9578T>C	p.Leu3193Pro	missense_variant	31/49	5	NM_002458.3	P1
MUC5B-AS1	ENST00000532061.2	n.56+3163A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3802 AN: 145142 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.0304

Gnomad EAS AF: 0.000212

Gnomad SAS AF: 0.00879

Gnomad FIN AF: 0.0717

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0247 AC: 6129 AN: 247974 Hom.: 149 AF XY: 0.0247 AC XY: 3320 AN XY: 134602

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00912

Gnomad FIN exome AF: 0.0707

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0279 AC: 40542 AN: 1454376 Hom.: 894 Cov.: 127 AF XY: 0.0274 AC XY: 19808 AN XY: 723712

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00913

Gnomad4 FIN exome AF: 0.0713

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0262 AC: 3801 AN: 145264 Hom.: 74 Cov.: 32 AF XY: 0.0266 AC XY: 1889 AN XY: 71058

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00788

Gnomad4 ASJ AF: 0.0304

Gnomad4 EAS AF: 0.000212

Gnomad4 SAS AF: 0.00881

Gnomad4 FIN AF: 0.0717

Gnomad4 NFE AF: 0.0338

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0357 Hom.: 364

Bravo AF: 0.0200

ESP6500AA AF: 0.0150 AC: 64

ESP6500EA AF: 0.0300 AC: 254

ExAC AF: 0.0239 AC: 2890

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	0.045
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.33
DANN	Benign	0.21
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00072	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.85	N
REVEL	Benign	0.013
Sift	Benign	0.18	T
Vest4		0.0090
ClinPred		0.0082	T
Varity_R		0.057
gMVP		0.21

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: rs117913875; hg19: chr11-1267688;