rs121908745

Positions:

• chr7-117559586-TATC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000492.4(CFTR):​c.1519_1521del​(p.Ile507del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 1,612,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★★). Synonymous variant affecting the same amino acid position (i.e. I506I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: CFTR NM_000492.4 inframe_deletion
• Clinical Significance: Pathogenic practice guideline P:27 O:1
• Conservation: PhyloP100: 8.79

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-117559586-TATC-T is Pathogenic according to our data. Variant chr7-117559586-TATC-T is described in ClinVar as [Pathogenic]. Clinvar id is 7106.Status of the report is practice_guideline, 4 stars. Variant chr7-117559586-TATC-T is described in Lovd as [Pathogenic]. Variant chr7-117559586-TATC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1519_1521del	p.Ile507del	inframe_deletion	11/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.221+1144_221+1146del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1519_1521del	p.Ile507del	inframe_deletion	11/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251266 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135794

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000760 AC: 111 AN: 1460626 Hom.: 0 AF XY: 0.0000771 AC XY: 56 AN XY: 726692

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

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: 0.0000927

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74310

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:12 Other:1

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The CFTR c.1519_1521delATC (p.I507del) variant has been reported in individuals with cystic fibrosis (PMID: 2236053; 1999342; 8092189). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 09, 2022	ACMG classification criteria: PS4 strong, PM2 moderated, PM3 very strong, PM4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 07, 2021	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This variant, c.1519_1521del, results in the deletion of 1 amino acid(s) of the CFTR protein (p.Ile507del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763199062, gnomAD 0.01%). This variant has been observed in individuals with cystic fibrosis (CF) (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 7106). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000492.3(CFTR):c.1519_1521delATC(aka I507del) is classified as pathogenic and is a classic variant in the context of cystic fibrosis. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.1519_1521delATC(aka I507del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2022	The p.I507del pathogenic mutation (also known as c.1519_1521delATC) is located in coding exon 11 of the CFTR gene. This pathogenic mutation results from an in-frame ATC deletion at nucleotide positions 1519 to 1521. This results in the in-frame deletion of an isoleucine at codon 507. This mutation was first reported in trans with p.F508del in an individual with cystic fibrosis (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). This mutation is associated with elevated sweat chloride levels, lung disease, pancreatic insufficiency, and Pseudomonas infection; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1994	- -

not provided Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	The CFTR c.1519_1521del; p.Ile507del (I507del) variant has been reported in multiple cystic fibrosis patients and is associated with pancreatic insufficiency (CFTR2 database, McKone 2003, Sosnay 2013). This variant is considered to cause cystic fibrosis when identified with another pathogenic variant on the opposite chromosome. References: CFTR2 database: http://cftr2.org/ McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 May 17;361(9370):1671-6. PMID: 12767731. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 13, 2018	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 08, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2021	In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Published functional studies demonstrate a damaging effect: decreased chloride conductance (Sosnay 2013); Observed multiple times with a pathogenic variant in patients with cystic fibrosis or disseminated bronchiectasis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Kerem 1990, Girodon 1997, McKone 2003); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31036917, 12767731, 31665830, 29261177, 25797027, 2236053, 18456578, 21228398, 22658665, 22975760, 9272738, 24440181, 23974870) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 12, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2014	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 30, 2017

Variant summary: The CFTR c.1519_1521delATC (p.Ile507del) variant involves the deletion of three nucleotides, leading to an in-frame deletion of a isoleucine residue in the ABC transporter-like and AAA+ ATPase domains (InterPro). One in silico tool predicts a damaging outcome for this variant. This variant was found in 10/276978 control chromosomes at a frequency of 0.0000361, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been identified in many CF patients and is considered a common variant, as it was found in 1.6% of CF alleles in a large, nationwide retrospective study (McKone_2003). Patients with this variant have a mean chloride conductance of 0.2% as of the WT CFTR (Sosnay_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 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

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908745; hg19: chr7-117199640;