rs79282516
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000492.4(CFTR):c.1438G>A(p.Gly480Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G480C) has been classified as Likely 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.1438G>A | p.Gly480Ser | missense_variant | 11/27 | ENST00000003084.11 | |
CFTR-AS1 | NR_149084.1 | n.221+1224C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1438G>A | p.Gly480Ser | missense_variant | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:5Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2017 | The p.G480S variant (also known as c.1438G>A), located in coding exon 11 of the CFTR gene, results from a G to A substitution at nucleotide position 1438. The glycine at codon 480 is replaced by serine, an amino acid with similar properties. This variant was identified in one individual with congenital absence of the vas deferens (CAVD); another CFTR alteration was not identified (Sharma H, et al. Mol. Hum. Reprod. 2014 Sep; 20(9):827-35). 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 available evidence to date, the clinical significance of this variant remains unclear. - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3, PM5_STR, PP3, PP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the CFTR protein (p.Gly480Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 20059485, 24958810, 26708955, 26730394). ClinVar contains an entry for this variant (Variation ID: 53254). 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. This variant disrupts the p.Gly480 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1376016, 7757078, 9150159, 26708955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 18, 2020 | - - |
CFTR-related disorder Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 18, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 15, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2021 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Co-observed with a second CFTR variant, phase unknown, in an individual with cystic fibrosis (Cao 2015) and observed in an individual with congenital absence of the vas deferens (Sharma 2014); This variant is associated with the following publications: (PMID: 24958810, 29261177, 26730394) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at