ENST00000654177.1:n.661G>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
• Publications: 479 publications found

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000654177.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000286275	ENST00000654177.1		n.661G>T		splice_region non_coding_transcript_exon	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

African (AFR) AF: 0.0206 AC: 854 AN: 41546

American (AMR) AF: 0.0850 AC: 1301 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3470

East Asian (EAS) AF: 0.00695 AC: 36 AN: 5178

South Asian (SAS) AF: 0.0849 AC: 410 AN: 4830

European-Finnish (FIN) AF: 0.115 AC: 1217 AN: 10590

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7499 AN: 67988

Other (OTH) AF: 0.0843 AC: 178 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		0.18

Splicing

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

Other links and lift over

dbSNP: rs35705950; hg19: chr11-1241221;