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rs77010898

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000492.4(CFTR):c.3846G>A(p.Trp1282Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,613,376 control chromosomes in the GnomAD database, including 1 homozygotes. 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

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic practice guideline P:30O:3

Conservation

PhyloP100: 9.42
Variant links:
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117642566-G-A is Pathogenic according to our data. Variant chr7-117642566-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7129.Status of the report is practice_guideline, 4 stars. Variant chr7-117642566-G-A is described in Lovd as [Pathogenic]. Variant chr7-117642566-G-A is described in Lovd as [Pathogenic]. Variant chr7-117642566-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.3846G>A p.Trp1282Ter stop_gained 23/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.3846G>A p.Trp1282Ter stop_gained 23/271 NM_000492.4 P2P13569-1
ENST00000456270.1 linkuse as main transcriptn.65+4785C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152130
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.0109
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.000458
AC:
115
AN:
250892
Hom.:
0
AF XY:
0.000442
AC XY:
60
AN XY:
135602
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00953
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000254
AC:
371
AN:
1461246
Hom.:
1
Cov.:
32
AF XY:
0.000268
AC XY:
195
AN XY:
726928
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00923
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000729
Gnomad4 OTH exome
AF:
0.000762
GnomAD4 genome
AF:
0.000329
AC:
50
AN:
152130
Hom.:
0
Cov.:
33
AF XY:
0.000363
AC XY:
27
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.0109
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000959
Alfa
AF:
0.000517
Hom.:
0
Bravo
AF:
0.000321
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000379
AC:
46
EpiCase
AF:
0.000218
EpiControl
AF:
0.000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:30Other:3
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:13Other:2
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_000492.3(CFTR):c.3846G>A(W1282) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.3846G>A(W1282) 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, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 29, 2019- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 18, 2018The CFTR c.3846G>A (p.Trp1282Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant was first reported by Vidaud et al. (1990) in one patient with cystic fibrosis who was a compound heterozygote for the p.Trp1282Ter variant and the common pathogenic p.Phe508del variant. Shoshani et al. (1992) later reported the p.Trp1282Ter variant on 63 chromosomes from 119 Israeli cystic fibrosis patients from 97 families, establishing the p.Trp1282Ter variant as the most common cystic fibrosis variant in the Ashkenazi Jewish population in Israel. Zielenski et al. (1995) published data from the Cystic Fibrosis Genetic Analysis Consortium showing that the p.Trp1282Ter variant appears in 535 of 43,849 CF chromosomes, with an overall frequency of 1.2%, and is the fifth most common disease-causing mutation in cystic fibrosis. ACMG guidelines published in 2004 recommend the p.Trp1282Ter variant be included in standard cystic fibrosis carrier screening. The variant is reported at a frequency of 0.00897 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Trp1282Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 15, 2014The Trp1282X variant in CFTR has been identified in numerous patients with cystic fibrosis (Viduad 1990, Kerem 1990, Hamosh 1991, Shoshani 1992). This variant is present on the American Board of Medical Genetics CFTR mutation panel (http://www.acmg.net/Pages/ACMG_Activities/stds-2002/cf.htm). This nonsense variant leads to a premature termination codon at position 1282, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity. -
Pathogenic, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 30, 2024This sequence change creates a premature translational stop signal (p.Trp1282*) 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 (rs77010898, gnomAD 0.9%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (CF). It is included in the American College of Medical Genetics (ACMG) panel of CF variants. It is one of the most common causes of cystic fibrosis. (PMID: 2475911, 15371902, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2475911, 15371902, 23974870). This variant is also known as W1282X. ClinVar contains an entry for this variant (Variation ID: 7129). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 30, 2003- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpretted as Pathogenic and reported on 11-16-2013 by Lab or GTR ID 320494. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, reviewed by expert panelresearchCFTR2Mar 17, 2017- -
Pathogenic, practice guidelinecurationAmerican College of Medical Genetics and Genomics (ACMG)Mar 03, 2004- -
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsNov 05, 2018- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 03, 2022The p.W1282* pathogenic mutation (also known as c.3846G>A), located in coding exon 23 of the CFTR gene, results from a G to A substitution at nucleotide position 3846. This changes the amino acid from a tryptophan to a stop codon within coding exon 23. This alteration was originally reported in two individuals with cystic fibrosis, one with p.F508del as the second mutation and the other with an unknown second mutation (Vidaud M et al. Hum Genet. 1990;85(4):446-449). This alteration is also associated with pancreatic insufficiency, elevated sweat chloride levels, and higher rate of Pseudomonas infection (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Of note, this alteration is also known as 3978G>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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 02, 2023Criteria applied: PVS1, PS3, PM3_VSTR, PM2_SUP -
not provided Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023CFTR: PVS1, PS4 -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 30, 2021The CFTR c.3846G>A (p.Trp1282*, or W1282X) variant causes the premature termination of CFTR protein synthesis. In the published literature, this variant is associated with severe pancreatic insufficient CF, classic CF, and is the most prevalent CF pathogenic variant in the Ashkenazi Jewish population (PMIDs: 29298718 (2018), 23951356 (2013), 21416780 2010), 1370365 (1992)). The frequency of this variant in the general population, 0.0097 (100/10360 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 15, 2023The CFTR c.3846G>A; p.Trp1282Ter variant (rs77010898) is reported in numerous individuals with cystic fibrosis and commonly associated with pancreatic insufficiency (see CFTR database, Kerem 1990, Shoshani 1992). This variant is also reported in ClinVar (Variation ID: 7129). It is observed in the general population with an overall allele frequency of 0.04% (121/282282 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/ Kerem BS et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. PMID: 2236053. Shoshani T et al. Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet. 1992 Jan;50(1):222-8. PMID: 1370365. -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 25, 2018- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 12, 2018The W1282X pathogenic variant in the CFTR gene is one of the most common variants associated with classic cystic fibrosis, including pancreatic insufficiency, when found in a homozygous state or when compound heterozygous with another CFTR pathogenic variant (Moskowitz et al., 2008; Kerem et al., 1990). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. W1282X was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The pathogenic variant was not present in the homozygous state within this population. We interpret W1282X as a pathogenic variant. -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 08, 2023- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicAug 23, 2021- -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1Other:1
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Pathogenic and reported on 03-06-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 05, 2017Variant summary: The CFTR c.3846G>A (p.Trp1282X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 46/120654 control chromosomes at a frequency of 0.0003813, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant is a common disease variant reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including CFTR2. Taken together, this variant is classified as pathogenic. -
Hereditary pancreatitis Pathogenic:1
Pathogenic, criteria provided, single submittercurationSema4, Sema4May 12, 2021- -
CFTR-related disorders Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 29, 2019- -
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 26, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.66
Cadd
Pathogenic
46
Dann
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A;A
Vest4
0.94
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77010898; hg19: chr7-117282620; COSMIC: COSV99069637; API