rs1554395323

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_000492.4(CFTR):c.3718-24_3873+601del variant causes a exon loss, splice acceptor, splice donor, splice region, 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: 33)

Consequence

CFTR
NM_000492.4 exon_loss, splice_acceptor, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 2.71

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]

CFTR links:

ENSG00000083622 (HGNC:):

ENSG00000083622 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035111412 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117642410-AAGTGATCCCATCACTTTTACCTTATAGGTGGGCCTCTTGGGAAGAACTGGATCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGAAATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAAGCCTTTGGAGTGATACCACAGGTGAGCAAAAGGACTTAGCCAGAAAAAAGGCAACTAAATTATATTTTTTACTGCTATTTGATACTTGTACTCAAGAAATTCATATTACTCTGCAAAATATATTTGTTATGCATTGCTGTCTTTTTTCTCCAGTGCAGTTTTCTCATAGGCAGAAAAGATGTCTCTAAAAGTTTGGAATTCTCAAATTCTGGTTATTGAAATGTTCATAGCTTTGATAGTGTTTTTCAGAAGACCAAATTTACAGTGGGAGCCTTGGGCTTTTGTTTTTTAACAGCTCTTTTTTGTTCCTGCTTCAGTGGCCTGACCTCCAAGTTAGCAATCGCCAGGTTGAGAAATGCTTTGCGAGACATAACAGATGCTCCTGAAATAACAAACACTTGGAATCATGAGGTAGTGGAATTGAAAATAGAAAGTGTAGTGATTGTTTTTTGTTATTTGGATGGGATGAACAATGTCAGATTAGTCTGTAACTATTTTTTTTTAATGTCACTCTGATTTGGTCACAAAGGATCTCTAGTCTCATTGCCTTAGTATCATTCTACGAATTAGAATGTGTTACTGTGTAAGAGCACTTCTTGTATATGAGAGAAATAGCAAC-A is Pathogenic according to our data. Variant chr7-117642410-AAGTGATCCCATCACTTTTACCTTATAGGTGGGCCTCTTGGGAAGAACTGGATCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGAAATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAAGCCTTTGGAGTGATACCACAGGTGAGCAAAAGGACTTAGCCAGAAAAAAGGCAACTAAATTATATTTTTTACTGCTATTTGATACTTGTACTCAAGAAATTCATATTACTCTGCAAAATATATTTGTTATGCATTGCTGTCTTTTTTCTCCAGTGCAGTTTTCTCATAGGCAGAAAAGATGTCTCTAAAAGTTTGGAATTCTCAAATTCTGGTTATTGAAATGTTCATAGCTTTGATAGTGTTTTTCAGAAGACCAAATTTACAGTGGGAGCCTTGGGCTTTTGTTTTTTAACAGCTCTTTTTTGTTCCTGCTTCAGTGGCCTGACCTCCAAGTTAGCAATCGCCAGGTTGAGAAATGCTTTGCGAGACATAACAGATGCTCCTGAAATAACAAACACTTGGAATCATGAGGTAGTGGAATTGAAAATAGAAAGTGTAGTGATTGTTTTTTGTTATTTGGATGGGATGAACAATGTCAGATTAGTCTGTAACTATTTTTTTTTAATGTCACTCTGATTTGGTCACAAAGGATCTCTAGTCTCATTGCCTTAGTATCATTCTACGAATTAGAATGTGTTACTGTGTAAGAGCACTTCTTGTATATGAGAGAAATAGCAAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53792.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3718-24_3873+601del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 23 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3718-27_3873+598del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 23 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Other:1

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 3 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_STR, PM2_SUP, PM3, PP4 -

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.