chr7-117559612-AAT-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.1545_1546del(p.Tyr515Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000479 in 1,461,168 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. E514E) 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.1545_1546del | p.Tyr515Ter | frameshift_variant | 11/27 | ENST00000003084.11 | |
CFTR-AS1 | NR_149084.1 | n.221+1119_221+1120del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1545_1546del | p.Tyr515Ter | frameshift_variant | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461168Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 726898
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Tyr515*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 1710601, 18456578, 20949073, 21520337, 26436105). This variant is also known as 1677delTA. ClinVar contains an entry for this variant (Variation ID: 7140). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1991 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2017 | Variant summary: The CFTR c.1545_1546delTA (p.Tyr515Terfs) variant (alternatively also known as 1677delTA) results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu671X, p.Lys710X, p.Glu1104X, etc.).This variant is absent in 121248 control chromosomes from ExAC. This variant is reported in numerous CF patients and is a common pathogenic variant in Black Sea region (Angelicheva_1994, Kanavakis_1995, Angelicheva_1997, Frentescu_2008, Castallani_2008, and Sosnay_2013). It has also been found in a CBAVD patient who had E831X on the other allele (Hinzpeter_2010). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 07, 2019 | NM_000492.3(CFTR):c.1545_1546delTA(Y515*, aka 1677delTA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1545_1546delTA(Y515*, aka 1677delTA) 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 | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 23, 2022 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2022 | The c.1545_1546delTA pathogenic mutation (also known as c.1677delTA), located in coding exon 11 of the CFTR gene, results from a deletion of two nucleotides at nucleotide positions 1545 to 1546, causing a translational frameshift with a predicted alternate stop codon (p.Y515*). This mutation has been reported in multiple patients with cystic fibrosis, including many homozygotes; it has been observed to be a common mutant allele in populations near the Southern Black Sea, Georgia in particular (Angelicheva D et al. Hum. Mutat., 1994;3:353-7; Onay T et al. Hum. Genet., 1998 Feb;102:224-30; Bonyadi M et al. Genet Test Mol Biomarkers 2011 Jan;15:89-92). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and Pseudomonas infection (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. - |
not provided Pathogenic:3
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 | Revvity Omics, Revvity | Aug 25, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
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 16, 2024 | - - |
Abnormality of metabolism/homeostasis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at