11-1256664-C-T

Variant names:

• chr11-1256664-C-T
• rs56310773
• NM_002458.3:c.16137-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.16137-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,555,898 control chromosomes in the GnomAD database, including 859 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 31)
  • Exomes 𝑓: 0.030 (796 hom.)
• Consequence: MUC5B NM_002458.3 splice_region, intron
• Scores: Splicing: ADA: 0.0008739
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.533

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]

MIR6744 (HGNC:50051): (microRNA 6744) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-1256664-C-T is Benign according to our data. Variant chr11-1256664-C-T is described in ClinVar as [Benign]. Clinvar id is 164008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1256664-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.025 (3790/151838) while in subpopulation NFE AF = 0.0327 (2217/67902). AF 95% confidence interval is 0.0315. There are 63 homozygotes in GnomAd4. There are 1885 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 3790 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5B	NM_002458.3	c.16137-7C>T		splice_region_variant, intron_variant	Intron 38 of 48	ENST00000529681.5	NP_002449.2
MIR6744	NR_106802.1	n.60C>T		non_coding_transcript_exon_variant	Exon 1 of 1
MIR6744	unassigned_transcript_1817	n.17C>T		non_coding_transcript_exon_variant	Exon 1 of 1
MIR6744	unassigned_transcript_1816	n.*36C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5B	ENST00000529681.5	c.16137-7C>T		splice_region_variant, intron_variant	Intron 38 of 48	5	NM_002458.3	ENSP00000436812.1
MIR6744	ENST00000619480.1	n.60C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3791 AN: 151720 Hom.: 63 Cov.: 31

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00748

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00790

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0226

GnomAD2 exomes AF: 0.0253 AC: 4211 AN: 166686 AF XY: 0.0247

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.00531

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0301 AC: 42234 AN: 1404060 Hom.: 796 Cov.: 30 AF XY: 0.0294 AC XY: 20390 AN XY: 694028

Gnomad4 AFR exome AF: 0.0118 AC: 374 AN: 31636

Gnomad4 AMR exome AF: 0.00565 AC: 202 AN: 35730

Gnomad4 ASJ exome AF: 0.0288 AC: 721 AN: 25012

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 36262

Gnomad4 SAS exome AF: 0.00965 AC: 763 AN: 79036

Gnomad4 FIN exome AF: 0.0723 AC: 3506 AN: 48524

Gnomad4 NFE exome AF: 0.0324 AC: 35092 AN: 1084014

Gnomad4 Remaining exome AF: 0.0266 AC: 1550 AN: 58178

GnomAD4 genome AF: 0.0250 AC: 3790 AN: 151838 Hom.: 63 Cov.: 31 AF XY: 0.0254 AC XY: 1885 AN XY: 74198

Gnomad4 AFR AF: 0.0131 AC: 0.0130834 AN: 0.0130834

Gnomad4 AMR AF: 0.00747 AC: 0.00746855 AN: 0.00746855

Gnomad4 ASJ AF: 0.0285 AC: 0.0285303 AN: 0.0285303

Gnomad4 EAS AF: 0.000193 AC: 0.000193498 AN: 0.000193498

Gnomad4 SAS AF: 0.00791 AC: 0.00790678 AN: 0.00790678

Gnomad4 FIN AF: 0.0692 AC: 0.0692133 AN: 0.0692133

Gnomad4 NFE AF: 0.0326 AC: 0.03265 AN: 0.03265

Gnomad4 OTH AF: 0.0224 AC: 0.0224023 AN: 0.0224023

Alfa AF: 0.0301 Hom.: 104

Bravo AF: 0.0198

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

16137-7C>T in intron 38 of MUC5B: This variant is not expected to have clinical significance because it has been identified in 3.0% (252/8296) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs56310773). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00087
dbscSNV1_RF	Benign	0.032
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: rs56310773; hg19: chr11-1277894;