rs76649725
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.3764C>A(p.Ser1255Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,402 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. S1255S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.3764C>A | p.Ser1255Ter | stop_gained | 23/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3764C>A | p.Ser1255Ter | stop_gained | 23/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.65+4867G>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251034Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135670
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461402Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726994
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2022 | The p.S1255* pathogenic mutation (also known as c.3764C>A), located in coding exon 23 of the CFTR gene, results from a C to A substitution at nucleotide position 3764. This changes the amino acid from a serine to a stop codon within coding exon 23. In one study, this mutation was seen in an individual with pancreatic disease, mild pulmonary involvement, and a second nonsense alteration confirmed in trans (Cutting GR et al. N. Engl. J. Med., 1990 Dec;323:1685-9). 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 | Mendelics | Nov 05, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 1990 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change creates a premature translational stop signal (p.Ser1255*) 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 (rs76649725, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 2233965, 26708955). ClinVar contains an entry for this variant (Variation ID: 7125). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 07, 2019 | NM_000492.3(CFTR):c.3764C>A(S1255*) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 26708955. Classification of NM_000492.3(CFTR):c.3764C>A(S1255*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2019 | The CFTR c.3764C>A; p.Ser1255Ter variant (rs76649725) is reported in the literature in multiple individuals affected with cystic fibrosis (Behar 2017, Cutting 1990, Macek 1997, CFTR2 database). In at least one affected individual, this variant was confirmed in trans to a second pathogenic variant (Cutting 1990). Several other reports indicate this variant also occurs in cis to a missense variant, p.Ile1203Val (Behar 2017, Cutting 1992). The p.Ser1255Ter variant is found on only two chromosomes (2/251034 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Cutting GR et al. Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians. Am J Hum Genet. 1992 Jun;50(6):1185-94. Cutting GR et al. Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. N Engl J Med. 1990 Dec 13;323(24):1685-9. Macek M Jr et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am J Hum Genet. 1997 May;60(5):1122-7. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 28, 2022 | PM2, PM3_strong, PVS1 - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2018 | Variant summary: CFTR c.3764C>A (p.Ser1255X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu1258fsX7, p.Trp1282X, p.Ile1295fsX32). The variant allele was found at a frequency of 4.1e-06 in 245776 control chromosomes (gnomAD). c.3764C>A has been reported in the literature in individuals affected with Cystic Fibrosis (Cutting_1992, Macek_1997, Sugarman_2004, Sontag_2016). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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 | Apr 20, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at