rs397508136

Positions:

• chr7-117480081-GCGCCCGAGAGACCATGCAGAGGT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000003084.11(CFTR):​c.-9_14del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR ENST00000003084.11 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117480081-GCGCCCGAGAGACCATGCAGAGGT-G is Pathogenic according to our data. Variant chr7-117480081-GCGCCCGAGAGACCATGCAGAGGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 53158.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117480081-GCGCCCGAGAGACCATGCAGAGGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.-9_14del		start_lost, 5_prime_UTR_variant	1/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.-9_14del		start_lost, 5_prime_UTR_variant	1/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461716 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 2018	The c.-9_14del23 pathogenic mutation, located in the 5' untranslated region and coding exon 1 of the CFTR gene, results from a deletion of 23 nucleotides at positions -9 to 14. This alters the methionine residue at the initiation codon (ATG). This mutation was detected in one individual with cystic fibrosis; however, complete genotype and phenotype information were not provided (Alonso MJ et al. Ann. Hum. Genet., 2007 Mar;71:194-201). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

The CFTR c.-9_14del23 variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in at least eight alleles in cystic fibrosis screening studies and has been identified in a cohort of patients with Cystic Fibrosis of Spanish ancestry (Beauchamp et al. 2019. PubMed ID: 31036917; Raraigh et al. 2021. PubMed ID: 34782259; Alonso et al. 2007. PubMed ID: 17331079). This variant is also referred to in the literature as c.124del23bp, using legacy nomenclature. This variant has not been reported in a large population database, indicating it is rare. In ClinVar, this variant is classified as pathogenic, including by the CF Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/53158/). This variant is interpreted as pathogenic. -

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: rs397508136; hg19: chr7-117120135;