chr7-117611555-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000492.4(CFTR):c.3140-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,312,924 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 Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
CFTR
NM_000492.4 intron
NM_000492.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.133
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 Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-117611555-A-G is Pathogenic according to our data. Variant chr7-117611555-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 35864.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611555-A-G is described in Lovd as [Pathogenic]. Variant chr7-117611555-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3140-26A>G | intron_variant | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3140-26A>G | intron_variant | 1 | NM_000492.4 | P2 | |||
ENST00000456270.1 | n.177+4674T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152118Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
9
AN:
152118
Hom.:
Cov.:
31
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: 0.0000423 AC: 10AN: 236632Hom.: 0 AF XY: 0.0000550 AC XY: 7AN XY: 127380
GnomAD3 exomes
AF:
AC:
10
AN:
236632
Hom.:
AF XY:
AC XY:
7
AN XY:
127380
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: 0.000108 AC: 125AN: 1160806Hom.: 0 Cov.: 16 AF XY: 0.000105 AC XY: 62AN XY: 591218
GnomAD4 exome
AF:
AC:
125
AN:
1160806
Hom.:
Cov.:
16
AF XY:
AC XY:
62
AN XY:
591218
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: 0.0000592 AC: 9AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74298
GnomAD4 genome
AF:
AC:
9
AN:
152118
Hom.:
Cov.:
31
AF XY:
AC XY:
4
AN XY:
74298
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:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:24
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 20, 2020 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 10425036) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 35864; PMID: 25910067; PMID: 25122143; PMID: 24243928; PMID: 23810505; PMID: 15365999; PMID: 28603918) - PS4. The variant is present at low allele frequencies population databases (rs76151804 – gnomAD 0.0004850%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.3140-26A>G was detected in trans with a pathogenic variant (PMID: 23810505; PMID: 28603918; PMID: 10425036) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000492.3(CFTR):c.3140-26A>G(aka 3272-26A>G) is classified as pathogenic and is a non-classic variant in the context of cystic fibrosis. Sources cited for classification include the following: PMID: 10425036 and 23974870. Classification of NM_000492.3(CFTR):c.3140-26A>G(aka 3272-26A>G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2022 | The c.3140-26A>G intronic pathogenic mutation (also known as 3272-26A>G) results from an A to G substitution 26 nucleotides upstream from coding exon 20 in the CFTR gene. This alteration has been shown to alter splicing and add 25 nucleotides to the final transcript, causing a premature translational stop codon (Beck S et al. Hum. Mutat., 1999;14:133-44). Another study demonstrated this pathogenic mutation, when in combination with p.F508del, decreased the amount of normal CFTR mRNA to 8.2% of total CFTR mRNA (Ramalho AS et al. Am. J. Respir. Cell Mol. Biol., 2002 Nov;27:619-27). In a cohort of 60 individuals with cystic fibrosis, this alteration was associated with a later presentation of disease, a reduced risk of pancreatic insufficiency, and better lung function (Amaral MD et al. J. Med. Genet., 2001 Nov;38:777-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change falls in intron 19 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs76151804, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 17481968, 23974870). It has also been observed to segregate with disease in related individuals. This variant is also known as 3272-26A>G. ClinVar contains an entry for this variant (Variation ID: 35864). Studies have shown that this variant alters CFTR gene expression (PMID: 12397022, 23974870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 20, 2023 | - - |
not provided Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 21, 2023 | The CFTR c.3140-26A>G (also known as 3272-26A>G) variant leads to the creation of an alternative splice acceptor site that competes with the normal splice site during RNA processing. The use of this alternative splice site results in the occurrence of an alternatively spliced mRNA with 25 extra nucleotides from intron 19 and a premature stop codon soon thereafter (PMID: 10425036 (1999)). In the published literature, this variant in compound heterozygous and homozygous state is associated with mild CF phenotype and pancreatic sufficiency (PMIDs: 34782259 (2021), 33855558 (2020), 22658665 (2012), 17481968 (2007), 11732487 (2001), 10425036 (1999), 7542347 (1995), 1379210 (1992)). The frequency of this variant in the general population, 0.00012 (4/34026 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CFTR c.3140-26A>G variant has been reported in several compound heterozygous cystic fibrosis (CF) patients who also carried the p.F508del variant or another pathogenic CFTR variant (Pereira_2019_ PMID: 30996306; Beck_1999_PMID:10425036; Ramalho_2002_PMID:12397022; Storm_2007_PMID:17481968). This variant has been reported to be associated with a milder CF phenotype (Beck_1999_PMID:10425036). The variant was identified in dbSNP (ID: rs76151804) and ClinVar (classified as pathogenic by Invitae, EGL Genetics and seven other submitters). The variant was identified in control databases in 13 of 268026 chromosomes at a frequency of 0.0000485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 4 of 34026 chromosomes (freq: 0.000118), European (non-Finnish) in 8 of 120280 chromosomes (freq: 0.000067) and African in 1 of 24118 chromosomes (freq: 0.000041), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), other, or South Asian populations. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. Multiple functional studies have confirmed this aberrant splicing and have determined that this variant extends exon 20 by 25 base pairs, which causes a frameshift leading to a premature stop codon (Sanz_2017_PMID: 28863137; Beck_1999_PMID:10425036; Ramalho_2002_PMID: 12397022). Compared to wild type, patient cells with this variant only have 5% normal CFTR mRNA (Ramalho_2002_PMID: 12397022). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 21, 2022 | PS3, PM3, PM2, PP3, PP5 - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 14, 2019 | The CFTR c.3140-26A>G variant (rs76151804), also known as 3272-26A>G, is reported in the literature in multiple patients diagnosed with cystic fibrosis (CF), typically with pancreatic sufficiency (Fanen 1992, Beck 1999, Amaral 2001, Ramalho 2002, Sosnay 2013, CFTR2 database), and in individuals with pancreatitis (Ooi 2012) or congenital bilateral absence of the vas deferens (Steiner 2011). Many affected individuals with this variant also carry a second pathogenic CFTR variant (Fanen 1992, Beck 1999, Ramalho 2002, Steiner 2011). The c.3140-26A>G variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 35864), and it is found in the general population with an overall allele frequency of 0.005% (13/268026 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic acceptor splice site. Messenger RNA analysis reveals that the variant causes aberrant splicing of the CFTR transcript, leading to the inclusion of 25 additional nucleotides of intron 17a (Beck 1999). This results in a premature stop codon at exon 17b, which results in the degradation of the majority of the aberrant CFTR transcript and only 4-5 percent of normal CFTR protein production compared to healthy individuals (Ramalho 2002, Sosnay 2013). Based on available evidence, the c.3140-26A>G variant is classified as pathogenic. References: CFTR2 Database: http://cftr2.org/ Amaral M et al. Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study. J Med Genet. 2001; 38(11):777-83. Beck S et al. Cystic fibrosis patients with the 3272-26A-->G mutation have mild disease, leaky alternative mRNA splicing, and CFTR protein at the cell membrane. Hum Mutat. 1999; 14(2):133-44. Fanen P et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992; 13(3):770-6. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Ramalho A et al. Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Am J Respir Cell Mol Biol. 2002; 27(5):619-27. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Steiner B et al Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD - |
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 | - - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 26
Find out detailed SpliceAI scores and Pangolin per-transcript scores at