rs56310773

Positions:

• chr11-1256664-C-T

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.16137-7C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0008739
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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

Verdict is Benign. Variant got -14 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_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3790 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.16137-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000529681.5
MIR6744	NR_106802.1	n.60C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.16137-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002458.3	P1
MIR6744	ENST00000619480.1	n.60C>T		mature_miRNA_variant	1/1

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

GnomAD3 exomes AF: 0.0253 AC: 4211 AN: 166686 Hom.: 88 AF XY: 0.0247 AC XY: 2215 AN XY: 89758

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 SAS exome AF: 0.00976

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

Gnomad4 AMR exome AF: 0.00565

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00965

Gnomad4 FIN exome AF: 0.0723

Gnomad4 NFE exome AF: 0.0324

Gnomad4 OTH exome AF: 0.0266

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

Gnomad4 AMR AF: 0.00747

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00791

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.0326

Gnomad4 OTH AF: 0.0224

Alfa AF: 0.0286 Hom.: 31

Bravo AF: 0.0198

Asia WGS AF: 0.00404 AC: 14 AN: 3478

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

Feb 21, 2013

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.50

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;