rs397508734
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.490-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,357,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000492.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.490-1G>A | splice_acceptor_variant | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.490-1G>A | splice_acceptor_variant | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249200Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134862
GnomAD4 exome AF: 0.00000295 AC: 4AN: 1357574Hom.: 0 Cov.: 21 AF XY: 0.00000294 AC XY: 2AN XY: 680942
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 14, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: CFTR c.490-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' splicing acceptor site, and three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 249200 control chromosomes (gnomAD). c.490-1G>A has been reported in the literature in individuals affected with Cystic Fibrosis who were reported as compound heterozygous with other pathogenic variants (Krzyzanowska_2015, Montgomery_2018). These data indicate that the variant is likely to 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: 26160248, 29884450). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change affects an acceptor splice site in intron 4 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508734, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 23857699, 26160248). This variant is also known as c.622-1G>A. ClinVar contains an entry for this variant (Variation ID: 53974). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 19, 2020 | This variant has been previously identified in patients with cystic fibrosis and is classified as likely pathogenic by one ClinVar submitter. It (rs397508734) is rare (<0.1%) in a large population dataset ( gnomAD: 4/249200 total alleles; 0.002%; no homozygotes). Bioinformatic analysis predicts that this canonical splice site variant would affect normal exon 4 splicing, although this has not been confirmed experimentally to our knowledge. We consider this variant to be pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2022 | The c.490-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 5 of the CFTR gene. This alteration was reported as compound heterozygous in two individuals with cystic fibrosis (CF) and pancreatic insufficiency (PI), moderate pulmonary disease, and elevated sweat chloride levels (Zielenski J et. al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids;1995). Additionally, this alteration was detected as compound heterozygous in an individual with CF, who had mild pulmonary disease and elevated sweat chloride levels (Krzyanowska P et al. Sci Rep, 2015 Jul;5:12000). This nucleotide position is highly conserved on sequence alignment. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at