rs78984783

Variant summary

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

The ENST00000003084.11(CFTR):​c.3528del​(p.Lys1177SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,613,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★★). Synonymous variant affecting the same amino acid position (i.e. T1176T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 frameshift

Scores

Not classified

Clinical Significance

Pathogenic practice guideline P:22O:1

Conservation

PhyloP100: -0.180
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 7-117627579-AC-A is Pathogenic according to our data. Variant chr7-117627579-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 35868.Status of the report is practice_guideline, 4 stars. Variant chr7-117627579-AC-A is described in Lovd as [Pathogenic]. Variant chr7-117627579-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CFTRNM_000492.4 linkuse as main transcriptc.3528del p.Lys1177SerfsTer15 frameshift_variant 22/27 ENST00000003084.11 NP_000483.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.3528del p.Lys1177SerfsTer15 frameshift_variant 22/271 NM_000492.4 ENSP00000003084 P2P13569-1
ENST00000456270.1 linkuse as main transcriptn.66-11240del intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000168
AC:
42
AN:
250746
Hom.:
0
AF XY:
0.000199
AC XY:
27
AN XY:
135496
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000277
Gnomad NFE exome
AF:
0.000309
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000179
AC:
262
AN:
1461064
Hom.:
0
Cov.:
32
AF XY:
0.000184
AC XY:
134
AN XY:
726812
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000487
Gnomad4 NFE exome
AF:
0.000194
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000567
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:22Other:1
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:11Other:1
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 testingAmbry GeneticsApr 05, 2022The c.3528delC pathogenic mutation, located in coding exon 22 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 3528, causing a translational frameshift with a predicted alternate stop codon (p.K1177Sfs*15). This alteration was identified in an individual with cystic fibrosis in conjunction with p.G551D (Adam RJ et al. JCI Insight, 2016 Apr;1:e86183). This alteration is also associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 3659delC 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, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 03, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 05, 2020The p.Lys1117SerfsX15 variant in CFTR (c.3528delC, also reported in the past as c.3659delC) is a well-established pathogenic variant in individuals with cystic fibrosis and is often associated with pancreatic insufficiency. It was classified as pathogenic on Mar 17, 2017 by the ClinGen-approved CFTR2 expert panel and is included in the ACMG Technical Standards and Guidelines for CFTR Mutation Testing (ClinVar Variation ID 35868) (Kerem 1990 PMID:2236053, Grody 2001 PMID:11280952, Sosnay 2013 PMID:23974870, Ooi 2012 PMID: 22658665). It has also been identified in 0.028% (36/128698) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1117 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis and other CFTR-related disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CFTR-related disorders. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting. -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 08, 2020- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityDec 08, 2020Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 12, 2019NM_000492.3(CFTR):c.3528delC(K1177Sfs*15, aka 3659delC) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3528delC(K1177Sfs*15, aka 3659delC) 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 testingLabcorp Genetics (formerly Invitae), LabcorpJan 13, 2024This sequence change creates a premature translational stop signal (p.Lys1177Serfs*15) 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 (rs762828343, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 15371902, 23974870). This variant is also known as c.3659delC . ClinVar contains an entry for this variant (Variation ID: 35868). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panelresearchCFTR2Mar 17, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsNov 05, 2018- -
not provided Pathogenic:6
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundOct 02, 2023- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 31, 2023The CFTR c.3528del, p.Lys1177SerfsTer15 variant (rs78984783), also known as 3659delC, is reported in the literature in numerous individuals affected with cystic fibrosis and is often associated with pancreatic insufficiency (Kerem 1990, Sosnay 2013, CFTR2 database). The variant is listed in ClinVar (Variation ID: 35868), and observed in the general population at a frequency of 0.016% (44/282148 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Kerem B 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; 87(21):8447-51. PMID: 2236053. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 30, 2023- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 13, 2017- -
CFTR-related disorder Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 14, 2024The CFTR c.3528delC variant is predicted to result in a frameshift and premature protein termination (p.Lys1177Serfs*15). This variant, also described as 3659delC, has previously been reported to be causative for cystic fibrosis (Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870; https://cftr2.org/). This variant is reported in 0.028% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMar 08, 2020- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs78984783; hg19: chr7-117267633; API