rs397508706

Positions:

• chr7-117666914-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.4251del​(p.Glu1418ArgfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 8.31

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117666914-GA-G is Pathogenic according to our data. Variant chr7-117666914-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 53933.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117666914-GA-G is described in Lovd as [Pathogenic]. Variant chr7-117666914-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.4251del	p.Glu1418ArgfsTer14	frameshift_variant	27/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.4251del	p.Glu1418ArgfsTer14	frameshift_variant	27/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727162

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 Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2023	ClinVar contains an entry for this variant (Variation ID: 53933). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with classic symptoms of Cystic Fibrosis (PMID: 7691344, 15638824, 23974870; www.CFTR2.org). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1418Argfs*14) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the CFTR protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2023	The c.4251delA pathogenic mutation (also known as 4382delA), located in coding exon 27 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 4251, causing a translational frameshift with a predicted alternate stop codon (p.E1418Rfs*14). This alteration occurs at the 3' terminus of the CFTR gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 63 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple individuals with cystic fibrosis and elevated sweat chloride levels (Claustres M et al. Hum. Mol. Genet., 1993 Aug;2:1209-13; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2017	Variant summary: The CFTR c.4251delA (p.Glu1418Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.4364C>G, p.Ser1455X; c.4426C>T, p.Gln1476X). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120796 control chromosomes. This variant was found in multiple CF patients with mean sweat chloride conc 60mM (Sosnay_Nature Genetics_2013) including in a patient in compound heterozigosity with c.3849+1G>A (not in our internal database) with a presentation characteristic of Pseudo-Bartters syndrome, a rare typical presentation of CF (Nahida_ActaPed_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including CFTR2 where it was reported in 62 patients, with an average of 103 mEq/L sweat chloride, (33% with PI, 40% with Pseudomonas infection). Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 20, 2020	PVS1_strong, PM2, PS3, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 21, 2018

The CFTR c.4251delA; p.Glu1418fs variant (rs397508706), also known as 4382delA, is reported in the literature in multiple individuals affected with cystic fibrosis, including in a compound heterozygous state with a known pathogenic CFTR allele (Castaldo 2005, Claustres 1993, Nahida 2011, Sermet-Gaudelus 2010, Sosnay 2013). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 53933), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the CFTR gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 14 amino acid residues not usually present. Based on available information, the p.Glu1418fs variant is considered to be pathogenic. References: Castaldo G et al. Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population. Ann Hum Genet. 2005 Jan;69(Pt 1):15-24. Claustres M et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209-13. Nahida el-R et al. Pseudo-Bartter's syndrome revealing cystic fibrosis in an infant caused by 3849 + 1G>A and 4382delA compound heterozygosity. Acta Paediatr. 2011 Nov;100(11):e234-5. Sermet-Gaudelus I et al. Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis. Thorax. 2010 Jun;65(6):539-44. Sosnay PR Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. -

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508706; hg19: chr7-117306968;