rs780187979
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000492.4(CFTR):c.2557A>G(p.Ile853Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I853I) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2557A>G | p.Ile853Val | missense_variant | Exon 15 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251334Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135858
GnomAD4 exome AF: 0.000112 AC: 163AN: 1460776Hom.: 0 Cov.: 29 AF XY: 0.0000963 AC XY: 70AN XY: 726758
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74318
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:4
The p.I853V variant (also known as c.2557A>G), located in coding exon 15 of the CFTR gene, results from an A to G substitution at nucleotide position 2557. The isoleucine at codon 853 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 853 of the CFTR protein (p.Ile853Val). This variant is present in population databases (rs780187979, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 439487). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. 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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not provided Uncertain:3
Variant summary: The CFTR c.2557A>G (p.Ile853Val) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 5/121246 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
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The CFTR c.2557A>G; p.Ile853Val variant (rs780187979), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 439487). This variant is found in the general population with an overall allele frequency of 0.004% (12/282688 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.189). Another variant at this codon (c.2557A>T; p.Ile853Phe) has been reported in a patient with congenital absence of the vas deferens, but its clinical significance was not determined (Dayangac 2004). Due to limited information, the clinical significance of the p.Ile853Val variant is uncertain at this time. References: Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004; 19(5):1094-100. PMID: 15070876. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at