7-117667022-C-T
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_000492.4(CFTR):c.4357C>T(p.Arg1453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,034 control chromosomes in the GnomAD database, including 6 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 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00039 ( 6 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
4
7
8
Clinical Significance
Conservation
PhyloP100: 1.61
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.022263259).
BP6
Variant 7-117667022-C-T is Benign according to our data. Variant chr7-117667022-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411121.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=2}.
BS2
High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.4357C>T | p.Arg1453Trp | missense_variant | Exon 27 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000237 AC: 36AN: 152156Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
36
AN:
152156
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251036Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135632
GnomAD3 exomes
AF:
AC:
34
AN:
251036
Hom.:
AF XY:
AC XY:
20
AN XY:
135632
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000390 AC: 570AN: 1461760Hom.: 6 Cov.: 31 AF XY: 0.000396 AC XY: 288AN XY: 727188
GnomAD4 exome
AF:
AC:
570
AN:
1461760
Hom.:
Cov.:
31
AF XY:
AC XY:
288
AN XY:
727188
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000236 AC: 36AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74448
GnomAD4 genome
AF:
AC:
36
AN:
152274
Hom.:
Cov.:
33
AF XY:
AC XY:
16
AN XY:
74448
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
26
Asia WGS
AF:
AC:
5
AN:
3476
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:16Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:6
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2022 | Observed in individuals with pancreatitis or bronchiectasis as well as in healthy controls (Lee et al., 2003; Fujiki et al., 2004; Keiles et al., 2006; Aoyagi et al., 2009; Kondo et al., 2015; Nakano et al., 2015; Iso et al., 2019; Fujita et al., 2022; Ni et al., 2022); Published functional studies demonstrate reduced channel opening probability, normal gene expression and splicing, and no significant effect on cAMP-activated anion exchange (Lee et al., 2003; Iso et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.4489C>T; This variant is associated with the following publications: (PMID: 20981092, 34996830, 35387941, 12952861, Jefri[thesis]2018, 20571109, Yoshimura[abstract]2012, 26089335, 25492507, 30992994, 22664493, 20879059, 19383231, 11504857, 17003641, 15121783, 12166651, 35313924, 22515107) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 21, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 20, 2020 | The CFTR c.4357C>T; p.Arg1453Trp variant (rs4148725) is reported in the literature in individuals with chronic pancreatitis and bronchiectasis, as well as in control individuals (Keiles 2006, Kondo 2015, Lee 2003, Nakano 2015). While one study reported significant enrichment of this variant in individuals with idiopathic pancreatitis (Kondo 2015), this study included a small number of subjects, and a second study did not observe significant enrichment among pancreatitis patients (Nakano 2015). The p.Arg1453Trp variant is reported in ClinVar (Variation ID: 411121) and is found in the East Asian population with an allele frequency of 0.1% (20/19892 alleles) in the Genome Aggregation Database. The arginine at codon 1453 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, chloride channel activity assays suggest that the p.Arg1453Trp variant exhibits a substantially reduced probability of opening, though this results in only a mild reduction in channel current (Lee 2003). Due to limited information, the clinical significance of the p.Arg1453Trp variant is uncertain at this time. References: Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. Lee JH et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 Sep 15;12(18):2321-32. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 24, 2021 | - - |
CFTR-related disorder Uncertain:4Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 22, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 25, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2024 | The CFTR c.4357C>T variant is predicted to result in the amino acid substitution p.Arg1453Trp. This variant has been reported in patients with idiopathic pancreatitis or bronchitis from Japan and Korea as well as in healthy individuals (Kondo et al. 2015. PubMed ID: 26089335; Kim et al. 2010. PubMed ID: 20879059; Lee et al. 2003. PubMed ID: 12952861). However, this variant does not appear to affect CFTR protein expression and results are conflicting on whether chloride channel activity is affected (Lee et al. 2003. PubMed ID: 12952861). This variant is reported in 0.10% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence. - |
Uncertain significance, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Feb 20, 2024 | - - |
Cystic fibrosis Uncertain:3Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2025 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 25, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2024 | The p.R1453W variant (also known as c.4357C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4357. The arginine at codon 1453 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was observed in a Korean patient with bronchiectasis, but also in two healthy control individuals. The authors demonstrated that although this variant had no effect on the expression of the protein, there was a reduction in chloride channel function (Lee JH, et al. Hum Mol Genet. 2003;12(18):2321-2332). This variant has been observed in multiple Japanese cohorts of individuals diagnosed with pancreatitis (Fujiki K et al. J Med Genet. 2004;41(5):e55; Kondo S et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2015 Aug;309:G260-9; Iso M et al. Hum Genome Var, 2019 Apr;6:17; Fujita S et al. Endocr J, 2022 Sep;69:1101-1108). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 14, 2020 | Variant summary: CFTR c.4357C>T (p.Arg1453Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 258140 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the maximum expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.0011 vs 0.013), allowing no conclusion about variant significance. However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0232 (in the jMorp database). This frequency is about 1.7-fold higher than the maximum expected for a pathogenic variant, suggesting the variant could be a benign polymorphism. Though the variant, c.4357C>T, has not been reported in the literature in individuals affected with Cystic Fibrosis (CF) or Congenital Bilateral Absence of the Vas Deferens (CBAVD), it was found in several Japanese patients with pancreatitis, and was also described in some patients affected with diffuse panbronchiolitis, bronchiectasis and asthma. These reports do not provide unequivocal conclusions about association of the variant with the reported disease phenotypes. In two Japanese case-control studies, this variant was not significantly overrepresented in pancreatitis patient cohorts compared to controls (Fujiki_2004, Nakano_2015). In two other studies however, the frequency of this variant was higher in pancreatitis patients than in controls, though the sample sizes were small (Kondo_2015, Iso_2019). Therefore, whether this variant is a risk variant to pancreatitis needs to be further investigated. In one ICP patient, this variant co-occurred with another pathogenic variant (c.194+2T>C) and a risk variant (c.101A>G/p.Asn34Ser) in the SPINK1 gene (Nakano_2015), suggesting this variant was not a primary cause of disease in the patient. One functional study has shown that this variant leads to 37% decrease in whole cell chloride currents due to significantly reduced (by 78%) channel opening probability (Lee_2003), but the clinical significance of this effect on the associated pathophysiology of disease is unclear. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. six as a VUS, and one as likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary pancreatitis Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 03, 2021 | - - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 12, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at