rs184724618
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000492.4(CFTR):c.3025G>A(p.Ala1009Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000546 in 1,613,174 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 5.92
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 Uncertain_significance. Variant got 2 ACMG points.
PM1
In a domain ABC transmembrane type-1 2 (size 296) in uniprot entity CFTR_HUMAN there are 53 pathogenic changes around while only 8 benign (87%) in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25241217).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.3025G>A | p.Ala1009Thr | missense_variant | Exon 19 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000856 AC: 13AN: 151910Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000956 AC: 24AN: 251160Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135732
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461152Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 726886
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GnomAD4 genome 0.0000855 AC: 13AN: 152022Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74310
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:6
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2021 | The p.A1009T variant (also known as c.3025G>A and 3157G>A), located in coding exon 19 of the CFTR gene, results from a G to A substitution at nucleotide position 3025. The alanine at codon 1009 is replaced by threonine, an amino acid with similar properties. This alteration was first reported in 2 Hispanic individuals with cystic fibrosis (CF); however, specific clinical information or the presence of a second alteration was not provided (Schrijver I et al. J Mol Diagn. 2005;7(2):289-99). This alteration has also been reported in a 31 year old female with idiopathic pancreatitis (Hamoir C et al. Digestion. 2013;87(4):229-39). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 21, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 07, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1009 of the CFTR protein (p.Ala1009Thr). This variant is present in population databases (rs184724618, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 15858154, 23751316, 31005549, 32784480). ClinVar contains an entry for this variant (Variation ID: 53631). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Apr 04, 2024 | - - |
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 09, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 01, 2020 | The CFTR c.3025G>A; p.Ala1009Thr variant (rs184724618) is reported in the literature in the heterozygous state in individuals affected with cystic fibrosis or pancreatitis, but without a clear association with disease (Hamoir 2013, Schrijver 2005). This variant is reported in ClinVar (Variation ID: 53631), and is found in the general population with an overall allele frequency of 0.0096% (24/251160 alleles) in the Genome Aggregation Database. The alanine at codon 1009 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ala1009Thr variant is uncertain at this time. References: Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013;87(4):229-239. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005;7(2):289-299. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 01, 2023 | PM2_moderate - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 18, 2024 | The CFTR c.3025G>A (p.Ala1009Thr) variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 15858154 (2005)), CFTR-related disorders (PMIDs: 35171259 (2022), 34996830 (2022), 23751316 (2013), 15858154 (2005)), and reportedly healthy individuals (PMIDs: 16251901 (2006), 16126774 (2005)). The frequency of this variant in the general population, 0.00029 (10/34500 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2020 | - - |
CFTR-related disorder Uncertain:3
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 09, 2024 | The CFTR c.3025G>A variant is predicted to result in the amino acid substitution p.Ala1009Thr. This variant has been identified in the heterozygous state in an individual with idiopathic pancreatitis (Hamoir et al. 2013. PubMed ID: 23751316), in a cohort of Hispanic individuals with clinical manifestations consistent with cystic fibrosis (Schrijver et al. 2005. PubMed ID: 15858154), and in the control population in a study of individuals with infertility (Morea et al. 2005. PubMed ID: 16126774). This variant was also reported to be associated with chronic bronchitis in smokers (Table S1, Saferali et al. 2022. PubMed ID: 34996830). This variant is reported in 0.029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 30, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2024 | Variant summary: CFTR c.3025G>A (p.Ala1009Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function.The variant allele was found at a frequency of 0.0001 in 253826 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.3025G>A has been reported in an individual affected with idiopathic pancreatitis (example, Hamoir_2013), individuals screening for CF (example, Schrijver_2005, Lefterova_2016, Bozdogan_2020) as well as in healthy individuals (example, Pompei_2006, Morea_2005, Terlizzi_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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: 25735457, 33572515, 32784480, 11504857, 26075876, 23751316, 26847993, 15536480, 16126774, 16251901, 15858154, 31005549). ClinVar contains an entry for this variant (Variation ID: 53631). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.
REVEL
Uncertain
Sift
Benign
D;.;.;D;.
Sift4G
Pathogenic
D;.;.;D;.
Polyphen
B;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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