11-1219991-G-T

Variant names:

• chr11-1219991-G-T
• rs35705950
• ENST00000654177.1:n.661G>T

Variant summary

Our verdict is Benign. The variant received -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: ENSG00000286275 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

ENSG00000286275 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286275	ENST00000654177.1	n.661G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 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 AC: 0.0205555 AN: 0.0205555

Gnomad4 AMR AF: 0.0850 AC: 0.0850327 AN: 0.0850327

Gnomad4 ASJ AF: 0.117 AC: 0.117291 AN: 0.117291

Gnomad4 EAS AF: 0.00695 AC: 0.00695249 AN: 0.00695249

Gnomad4 SAS AF: 0.0849 AC: 0.0848861 AN: 0.0848861

Gnomad4 FIN AF: 0.115 AC: 0.11492 AN: 0.11492

Gnomad4 NFE AF: 0.110 AC: 0.110299 AN: 0.110299

Gnomad4 OTH AF: 0.0843 AC: 0.0842803 AN: 0.0842803

Alfa AF: 0.0545 Hom.: 108

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

May 13, 2022

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Differences in plasma levels of MUC5B according to genotypes -

not provided Benign:1

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUC5B: BS1, BS2 -

Interstitial lung disease 2 Other:1

Mar 04, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: risk factor

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Antisynthetase syndrome Other:1

May 15, 2024

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

Usual Interstitial Pneumonia was observed in the patients -

Pulmonary fibrosis, idiopathic, susceptibility to Other:1

Jun 06, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;