rs121908765
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.3612G>A(p.Trp1204Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,142 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 (★★★). Variant results in nonsense mediated mRNA decay.
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.3612G>A | p.Trp1204Ter | stop_gained | 22/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3612G>A | p.Trp1204Ter | stop_gained | 22/27 | 1 | NM_000492.4 | P2 | |
ENST00000456270.1 | n.66-11325C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250264Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135208
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461142Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726872
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2022 | The p.W1204* pathogenic mutation (also known as c.3612G>A and 3744G>A), located in coding exon 22 of the CFTR gene, results from a G to A substitution at nucleotide position 3612. This changes the amino acid from a tryptophan to a stop codon within exon 22. The c.3612G>A mutation was identified in an individual who presented with classic cystic fibrosis (CF) symptoms (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). The p.W1204* pathogenic mutation was described in a one individual with CF confirmed in trans with p.F508del (Ghanem N, Genomics 1994 May; 21(2):434-6). In a study of California Hispanic and African American individuals with CF and at least one unidentified mutant allele, this mutation was identified on five CF chromosomes (Alper OM, Hum. Mutat. 2004 Oct; 24(4):353). This pathogenic mutation is associated with elevated sweat chloride levels, decreased lung function, pancreatic insufficiency, and Pseudomonas infection (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7; The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 7, 2022). 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 | Jul 03, 2019 | Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 09, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Trp1204*) 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 (rs121908765, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7522211, 23974870). ClinVar contains an entry for this variant (Variation ID: 53779). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 03, 2013 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2018 | Variant summary: CFTR c.3612G>A (p.Trp1204X) 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 observed with an allele frequency of 1.2e-05 in 245006 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (1.2e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.3612G>A, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Sosnay_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submssions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cystic fibrosis;na:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both - |
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 | Aug 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at