chr7-117559609-A-G
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.1538A>G(p.Asp513Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D513E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1538A>G | p.Asp513Gly | missense_variant | Exon 11 of 27 | ENST00000003084.11 | NP_000483.3 | |
CFTR-AS1 | NR_149084.1 | n.221+1124T>C | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251190 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461128Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 726902 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:3Uncertain:1Other:1
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 513 of the CFTR protein (p.Asp513Gly). This variant is present in population databases (rs397508225, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10651488, 23974870, 33572515). ClinVar contains an entry for this variant (Variation ID: 53280). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
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Variant summary: CFTR c.1538A>G (p.Asp513Gly) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 251190 control chromosomes (gnomAD). c.1538A>G has been observed in multiple individuals affected with Cystic Fibrosis or CBAVD (e.g., Bienvenu_1998, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 4% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). ClinVar contains an entry for this variant (Variation ID: 53280). Based on the evidence outlined above, the variant was classified as pathogenic. -
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The p.D513G pathogenic mutation (also known as c.1538A>G), located in coding exon 11 of the CFTR gene, results from an A to G substitution at nucleotide position 1538. The aspartic acid at codon 513 is replaced by glycine, an amino acid with similar properties. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variant(s) in individual(s) with features consistent with cystic fibrosis; in at least one instance, the variants were identified in trans (Ambry internal data). In an assay testing CFTR function, this variant showed a functionally abnormal result (Bihler H et al. J Cyst Fibros, 2024 Jul;23:664-675). This variant has <10% of wild type quantity and function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/28/2025). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/28/2025). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
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Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1
the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at