rs1554395323

Positions:

• chr7-117642410-AAGTGATCCCATCACTTTTACCTTATAGGTGGGCCTCTTGGGAAGAACTGGATCAGGGAAGAGTACTTTGTTATCAGCTTTTTTGAGACTACTGAACACTGAAGGAGAAATCCAGATCGATGGTGTGTCTTGGGATTCAATAACTTTGCAACAGTGGAGGAAAGCCTTTGGAGTGATACCACAGGTGAGCAAAAGGACTTAGCCAGAAAAAAGGCAACTAAATTATATTTTTTACTGCTATTTGATACTTGTACTCAAGAAATTCATATTACTCTGCAAAATATATTTGTTATGCATTGCTGTCTTTTTTCTCCAGTGCAGTTTTCTCATAGGCAGAAAAGATGTCTCTAAAAGTTTGGAATTCTCAAATTCTGGTTATTGAAATGTTCATAGCTTTGATAGTGTTTTTCAGAAGACCAAATTTACAGTGGGAGCCTTGGGCTTTTGTTTTTTAACAGCTCTTTTTTGTTCCTGCTTCAGTGGCCTGACCTCCAAGTTAGCAATCGCCAGGTTGAGAAATGCTTTGCGAGACATAACAGATGCTCCTGAAATAACAAACACTTGGAATCATGAGGTAGTGGAATTGAAAATAGAAAGTGTAGTGATTGTTTTTTGTTATTTGGATGGGATGAACAATGTCAGATTAGTCTGTAACTATTTTTTTTTAATGTCACTCTGATTTGGTCACAAAGGATCTCTAGTCTCATTGCCTTAGTATCATTCTACGAATTAGAATGTGTTACTGTGTAAGAGCACTTCTTGTATATGAGAGAAATAGCAAC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The ENST00000003084.11(CFTR):​c.3718-24_3873+601del variant causes a splice acceptor, splice donor, splice donor 5th base, coding sequence, 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 ENST00000003084.11 splice_acceptor, splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 2.71

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]

(HGNC:):

ACMG classification

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 0.034886338 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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3718-24_3873+601del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	23/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3718-24_3873+601del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	23/27	1	NM_000492.4	ENSP00000003084	P2
	ENST00000456270.1	n.65+4160_65+4940del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	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 -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554395323; hg19: chr7-117282464;