rs397508809

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000492.4(CFTR):​c.870-1113_870-1110delGAAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CFTR
NM_000492.4 intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 1.26
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 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117538986-AGAAT-A is Pathogenic according to our data. Variant chr7-117538986-AGAAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CFTRNM_000492.4 linkuse as main transcriptc.870-1113_870-1110delGAAT intron_variant ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.870-1113_870-1110delGAAT intron_variant 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:2Other:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 12, 2023For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19759008). ClinVar contains an entry for this variant (Variation ID: 54075). This variant has been observed in individuals with cystic fibrosis (PMID: 19759008, 21783433). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -
not provided, no classification providedliterature onlyClinVar Staff, National Center for Biotechnology Information (NCBI)-- -
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 07, 2017The c.870-1110_870-1113delGAAT intronic variant, located in intron 7 of the CFTR gene, results from a deletion of 4 nucleotides within intron 7 of the CFTR gene. Two studies evaluating mRNA from patients' nasal epithelial cells revealed the inclusion of 97 base pairs of intron 7 sequence between exons 7 and 8 (Faà V et al. J. Biol. Chem., 2009 Oct;284:30024-31; Costa C et al. J. Cyst. Fibros., 2011 Dec;10:479-82). A minigene assay of wild-type and mutant constructs further demonstrated that this deletion abolished the binding site for hnRNPA2/B1 and created a binding site for SRp75 splicing factor (Faà V et al. J. Biol. Chem., 2009 Oct;284:30024-31). Multiple patients, mostly of Italian or French origin, have been described to be heterozygous for this alteration and a second pathogenic mutation; methods for phasing (cis vs. trans) were not described. Reported phenotypes and age at diagnosis have varied, but are most consistent with classic cystic fibrosis (Faà V et al. J. Biol. Chem., 2009 Oct;284:30024-31; Costa C et al. J. Cyst. Fibros., 2011 Dec;10:479-82). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 21, 2023- -
Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.29
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.29
Position offset: -48

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: rs397508809; hg19: chr7-117179040; API