rs397508522
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000492.4(CFTR):c.325T>A(p.Tyr109Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y109?) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.325T>A | p.Tyr109Asn | missense_variant | 4/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.325T>A | p.Tyr109Asn | missense_variant | 4/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251124Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135704
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461516Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727056
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | This variant is present in population databases (rs397508522, gnomAD 0.0009%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr109 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32539862). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt CFTR protein function. ClinVar contains an entry for this variant (Variation ID: 53695). This missense change has been observed in individuals with cystic fibrosis (PMID: 11555145, 15591474). This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 109 of the CFTR protein (p.Tyr109Asn). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2022 | The p.Y109N variant (also known as c.325T>A), located in coding exon 4 of the CFTR gene, results from a T to A substitution at nucleotide position 325. The tyrosine at codon 109 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been identified in individuals with a clinical diagnosis of cystic fibrosis (Rodman DM et al. Am J Respir Crit Care Med, 2005 Mar;171:621-6; Abou Alaiwa MH et al. J Cyst Fibros, 2014 Jul;13:373-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 23, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 03, 2023 | Variant summary: CFTR c.325T>A (p.Tyr109Asn) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251124 control chromosomes (gnomAD). c.325T>A has been reported in the literature in individuals affected with Cystic Fibrosis, including at least one patient who had a late diagnosis and an individual with intermmediate sweat chloride levels (e.g. Dragomir_2001, Schaedel_2002, Rodman_2005, Abou Alaiwa_2014, Raraigh_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12001283, 24418186, 11555145, 34782259, 15591474). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at