11-1219991-G-T

Position:

• chr11-1219991-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000654177.1(ENSG00000286275):​n.661G>T variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 152,220 control chromosomes in the GnomAD database, including 596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (★★).

• Frequency: Genomes: 𝑓 0.079 (596 hom., cov: 33)
• Consequence: ENST00000654177.1 splice_region, non_coding_transcript_exon
• Clinical Significance: Benign; risk factor criteria provided, multiple submitters, no conflicts U:1 B:1 O:3
• Conservation: PhyloP100: 0.183

Genes affected

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-1219991-G-T is Benign according to our data. Variant chr11-1219991-G-T is described in ClinVar as [Benign, risk_factor]. Clinvar id is 30126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000654177.1	n.661G>T		splice_region_variant, non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.0794 AC: 12074 AN: 152102 Hom.: 595 Cov.: 33

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0851

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00694

Gnomad SAS AF: 0.0838

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0861

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0793 AC: 12074 AN: 152220 Hom.: 596 Cov.: 33 AF XY: 0.0803 AC XY: 5978 AN XY: 74428

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.0850

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.00695

Gnomad4 SAS AF: 0.0849

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0843

Alfa AF: 0.0264 Hom.: 28

Bravo AF: 0.0747

ClinVar

Significance: Benign; risk factor

Submissions summary: Uncertain:1 Benign:1 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Susceptibility to coronavirus disease (COVID-19) severity and mortality due to low plasma levels of MUC5B Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 13, 2022

Differences in plasma levels of MUC5B according to genotypes -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

MUC5B: BS1, BS2 -

Antisynthetase syndrome Other:1

association, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 15, 2024

Usual Interstitial Pneumonia was observed in the patients -

Interstitial lung disease 2 Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2020

MUC5B c.-3133G>T has been associated with increased risk for idiopathic pulmonary fibrosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (16.2%, Genome Aggregation Database (gnomAD); rs35705950) and is present in ClinVar (ID: 30126). Several studies have reported an odds ratios between 3.7-8.3 for developing pulmonary fibrosis in heterozygous individuals (OR=6.3 [95% CI 4.6-8.7] Borie 2013, OR=6.3 [95% CI 3.1-12.7] Hunninghake 2013, OR=8.3 [95% CI 5.8-11.9] Seibold 2013, OR=4.9 [95% CI 3.42-7.03] Stock 2013, OR=5.72 [95% CI 4.7-7.1] Lee 2015, OR=6.2 [95% CI 5.14-7.48] Zhu 2015) and odds ratios between 11.3-21.7 for developing pulmonary fibrosis in homozygous individuals (OR=21.7 [95% CI 104-45.3] Borie 2013, OR=12.98 [95% CI 7.97-21.12] Lee 2015, OR=11.29 [95% CI 5.69-22.40] Zhu 2015). MUC5B c.-3133G>T is a promoter variant that results in increased MUC5B expression (Seibold 2011, Nakano 2016, Kaur 2017). In summary, this variant is an established risk factor for idiopathic pulmonary fibrosis. -

Pulmonary fibrosis, idiopathic, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 06, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.3
DANN	Benign	0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35705950; hg19: chr11-1241221;