7-117534366-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000492.4(CFTR):c.579+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,482,946 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 1 hom. )
Consequence
CFTR
NM_000492.4 splice_donor, intron
NM_000492.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.08
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02003151 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117534366-G-T is Pathogenic according to our data. Variant chr7-117534366-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 38494.Status of the report is practice_guideline, 4 stars. Variant chr7-117534366-G-T is described in Lovd as [Pathogenic]. Variant chr7-117534366-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.579+1G>T | splice_donor_variant, intron_variant | ENST00000003084.11 | NP_000483.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.579+1G>T | splice_donor_variant, intron_variant | 1 | NM_000492.4 | ENSP00000003084.6 |
Frequencies
GnomAD3 genomes 0.0000394 AC: 6AN: 152108Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000480 AC: 12AN: 249982Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135240
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GnomAD4 exome AF: 0.0000376 AC: 50AN: 1330838Hom.: 1 Cov.: 21 AF XY: 0.0000403 AC XY: 27AN XY: 669848
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GnomAD4 genome 0.0000394 AC: 6AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74314
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: practice guideline
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:7Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2021 | The c.579+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This mutation has been described in three siblings who presented with severe pulmonary symptoms, growth retardation, and pancreatic insufficiency and who also carried the c.489+1G>T mutation (De Braekeleer M et al. Clin Genet. 1997;51(3):214-216). In vitro studies of mRNA isolated from the nasal epithelial cells of a pancreatic insufficient CF patient who also carried the c.579+1G>T mutation, suggested that this mutation results in a transcript missing exon 5 (Zielenski J et al. Hum Mol Genet 1993;2(6):683-7). This mutation is typically associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). Of note, this alteration is also referred to as 711+1G>T in the literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
| Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | This sequence change affects a donor splice site in intron 5 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs77188391, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (CF) (PMID: 1710599, 20880762, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 711+1G>T. ClinVar contains an entry for this variant (Variation ID: 38494). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 11, 2019 | NM_000492.3(CFTR):c.579+1G>T(aka 711+1G>T) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.579+1G>T(aka 711+1G>T) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 19, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 31, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 19, 2018 | Variant summary: CFTR c.579+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site and one predicts the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 275871 control chromosomes (gnomAD and publications). c.579+1G>T has been reported in the literature in multiple individuals affected with Classic Cystic Fibrosis (McKone_2003, Zielenski_1991, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
CFTR-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 03, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at