rs121908789
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.3773dup(p.Leu1258PhefsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A1256A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3773dup | p.Leu1258PhefsTer7 | frameshift_variant | 23/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3773dup | p.Leu1258PhefsTer7 | frameshift_variant | 23/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.65+4863_65+4864insA | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251050Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135678
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461394Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727004
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74304
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 09, 2019 | NM_000492.3(CFTR):c.3773dupT(L1258Ffs*7, aka 3905insT) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 19724303 and 23974870. Classification of NM_000492.3(CFTR):c.3773dupT(L1258Ffs*7, aka 3905insT) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Nov 11, 2020 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 30, 2023 | The c.3773dupT pathogenic mutation (also known as c.3773_3774insT and 3905insT), located in coding exon 23 of the CFTR gene, results from a duplication of T at nucleotide position 3773, causing a translational frameshift with a predicted alternate stop codon (p.L1258Ffs*7). This mutation was described in 30 compound heterozygous individuals with cystic fibrosis characterized by elevated sweat chloride levels, failure to thrive, pancreatic insufficiency, and progressively decreasing lung function (Schibler A et al. Eur. Respir. J., 2001 Jun;17:1181-6). Immunocytochemical studies demonstrated that this alteration significantly reduces the amount of mature CFTR protein found in the apical membranes of nasal epithelia (Sanz J et al. Eur. J. Hum. Genet., 2010 Feb;18:212-7). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 3 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_STR, PS3_MOD, PM2_SUP, PM3_STR, PP4 - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Leu1258Phefs*7) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs796566397, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 19724303, 21520337, 23974870). This variant is also known as 3905insT. ClinVar contains an entry for this variant (Variation ID: 38726). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | CFTR: PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 17, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 08, 2022 | The CFTR c.3773dupT; p.Leu1258PhefsTer7 (rs387906370) variant, also known as 3905insT, is reported in multiple individuals diagnosed with cystic fibrosis (Dork 1994, Gallati 2009, Hirtz 2004, Sosnay 2013) and is generally associated with pancreatic insufficiency (Ooi 2012, Sosnay 2013, CFTR2 database). Functional characterization of the variant indicates that the transcript is insensitive to nonsense-medicated decay or nonsense-associated alternative splicing (Sanz 2010). The variant protein fails to mature and localize to the cell surface (Sanz 2010), resulting in severe reduction in chloride transport activity (Hirtz 2004). This variant is also reported in the ClinVar database (Variation ID: 38726). It is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant introduces a frameshift, and functional studies indicate it results in a truncated, inactive protein. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994; 94(5):533-42. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004; 2004 Oct;127(4):1085-95. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sanz J et al. The CFTR frameshift mutation 3905insT and its effect at transcript and protein level. Eur J Hum Genet. 2010; 18(2):212-7. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 01, 2021 | The frameshift variant causes the premature termination of CFTR protein synthesis. This variant causes cystic fibrosis (CF) when co-occurring with a CF-causing variant in trans and has also been reported in individuals affected with chronic pancreatitis in the published literature (PMID: 7525450 (1994), 23974870 (2013), 21520337 (2011), 19724303 (2010)). Additionally, immunohistochemical staining of the CFTR protein in patient nasal epithelial cells revealed that this variant significantly impairs expression (PMID: 19724303 (2010)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 20, 2021 | - - |
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 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at