rs369326781
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_ModerateBP6_Very_Strong
The NM_000492.4(CFTR):c.-4G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
CFTR
NM_000492.4 5_prime_UTR
NM_000492.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.51
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 -8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.27).
BP6
Variant 7-117480091-G-C is Benign according to our data. Variant chr7-117480091-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 53157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.-4G>C | 5_prime_UTR_variant | 1/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084 | c.-4G>C | 5_prime_UTR_variant | 1/27 | 1 | NM_000492.4 | ENSP00000003084.6 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251160Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135758
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GnomAD4 exome AF: 0.000157 AC: 230AN: 1461732Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114AN XY: 727176
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74258
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystic fibrosis Benign:4
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 14, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2018 | This alteration is classified as likely 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. - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CFTR: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 13, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 10, 2023 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 18, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2024 | Variant summary: CFTR c.-4G>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 7.6e-05 in 251160 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (7.6e-05 vs 0.013), allowing no conclusion about variant significance. c.-4G>C has been reported in CF patients who had F508del on the other chromosome (e.g. Zielenski_1991, Hadd_2004). Sickkids database references the variant in strong association with R117H. The variant was reportedly identified in cis with T5, R117H and R117H-T5 complex alleles (Hadd_2004; Lucarelli_2012; Regan_2015). Internal data support this observation with the variant being identified with R117H or R117H and T5 variants in the vast majority of tested samples. c.-4G>C has been reported to co-occur with two other pathogenic variants in multiple samples (data from internal testing and ClinVar). Lastly, the variant of interest has been described as polymorphism in published reports (e.g. Miller_1996). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1710599, 8659542, 15507674, 25739099, 26436105, 32483343). ClinVar contains an entry for this variant (Variation ID: 53157). Based on the evidence outlined above, the variant was classified as likely benign. - |
CFTR-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 27, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at