rs397508173
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.11C>A(p.Ser4Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,706 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S4S) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.11C>A | p.Ser4Ter | stop_gained | 1/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.11C>A | p.Ser4Ter | stop_gained | 1/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461706Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727160
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 11, 2017 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change creates a premature translational stop signal (p.Ser4*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508173, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7684643, 25176415). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53211). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2021 | The p.S4* pathogenic mutation (also known as c.11C>A), located in coding exon 1 of the CFTR gene, results from a C to A substitution at nucleotide position 11. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration has been described in trans with a pathogenic mutation in several patients with pancreatic insufficiency, elevated sweat chloride levels, gastrointestinal symptoms, and pulmonary disease (Glavac D et al. Hum Mol Genet 1993 Mar;2(3):315-6 and , Desgeorges M et al. Hum. Genet. 1997; 100:279-83). A further study determined that this mutation accounted for 7% of Lebanese CF alleles (Farra C et al. J. Cyst. Fibros. 2010; 9:406-10). This alteration is also known as c.143C>A in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 16, 2019 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 01, 2018 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 23, 2018 | Variant summary: CFTR c.11C>A (p.Ser4X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 120812 control chromosomes (ExAC). c.11C>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Cabello_2005, D'Apice_2004, Desgeorges_1997, Faria_2016). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
CFTR-related disorders Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 20, 2019 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 28, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at