rs181008242
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The ENST00000546407.1(CFTR):n.166+3475T>G variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 152,176 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0037 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CFTR
ENST00000546407.1 intron, non_coding_transcript
ENST00000546407.1 intron, non_coding_transcript
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.700
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
?
Variant 7-117479283-T-G is Benign according to our data. Variant chr7-117479283-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51029.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=3, Likely_benign=1}.
BS2
?
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000546407.1 | n.166+3475T>G | intron_variant, non_coding_transcript_variant | 1 | |||||
CFTR | ENST00000446805.2 | c.-486T>G | 5_prime_UTR_variant | 2/6 | 4 | ||||
CFTR | ENST00000673785.1 | c.-406+13452T>G | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00373 AC: 567AN: 152058Hom.: 3 Cov.: 32
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 86Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 70
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GnomAD4 genome ? AF: 0.00372 AC: 566AN: 152176Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242AN XY: 74384
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 03, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2018 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 15, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | - - |
not provided Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | CFTR: BS1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 22, 2023 | The CFTR variant c.-812T>G has been reported in the published literature in individuals affected with CF (PMIDs: 30296588 (2018), 23470247 (2013), 7540587 (1995)), CBAVD (PMID: 23470247 (2013)), and other CF-related disorders (PMIDs: 25797027 (2015), 18703788 (2008)). Functional studies show conflicting data, and the variant may affect CFTR promoter activity (PMIDs: 30296588 (2018), 25797027 (2015), 23470247 (2013), 7540587 (1995)). The frequency of this variant in the general population, 0.0052 (81/15406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | The CFTR c.-812T>G variant (rs181008242) is reported in the literature in individuals affected with CFTR-related disorders such as pancreatitis or congenital bilateral absence of the vas deferens (Giordano 2013, Mak 1999, Wilschanski 2006). This variant is also reported in ClinVar (Variation ID: 51029), and is found in the general population with an overall allele frequency of 0.34% (108/31356 alleles) in the Genome Aggregation Database. This variant occurs in the upstream promoter region at a nucleotide that is weakly conserved, but in vitro functional assays are conflicting for the effects on transcription and transcription factor binding (Bergougnoux 2015, Giordano 2013, Kerschner 2019). While this variant is not associated with classic cystic fibrosis, the clinical significance for CFTR-related disorders is uncertain. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015 Sep;14(5):646-53. PMID: 25797027. Giordano S et al. Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. J Mol Diagn. 2013 May;15(3):331-40. PMID: 23470247. Kerschner JL et al. Screening for Regulatory Variants in 460 kb Encompassing the CFTR Locus in Cystic Fibrosis Patients. J Mol Diagn. 2019 Jan;21(1):70-80. PMID: 30296588. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. PMID: 10376575. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. PMID: 16840743. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 18, 2017 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at