chr7-117548802-TG-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.1373delG(p.Gly458AspfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,150 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. G458G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1373delG | p.Gly458AspfsTer11 | frameshift_variant | Exon 10 of 27 | ENST00000003084.11 | NP_000483.3 | |
CFTR-AS1 | NR_149084.1 | n.222-6264delC | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000410 AC: 1AN: 243890 AF XY: 0.00000757 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1AN: 1458390Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 725320 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74322 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:6
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For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53237). This variant is also known as 1504delG. This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 9150159). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gly458Aspfs*11) 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). -
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The c.1373delG pathogenic mutation, located in coding exon 10 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 1373, causing a translational frameshift with a predicted alternate stop codon (p.G458Dfs*11). This variant has been identified in conjunction with another CFTR variant in an individual who met clinical criteria for cystic fibrosis (McCravy MS et al. Eur Respir J, 2020 Jul;56:). 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. -
Variant summary: CFTR c.1373delG (p.Gly458AspfsX11) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 244091 control chromosomes, predominantly at a frequency of 6.5e-05 within the African or African-American subpopulation in the gnomAD database. c.1373delG has been reported in the literature in an African American individual affected with Cystic Fibrosis (example, Macek_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9150159, 16049310). Multiple clinical diagnostic laboratories and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at