7-117587738-G-A

Variant names:

• chr7-117587738-G-A
• rs76713772
• NM_000492.4:c.1585-1G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1585-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,586,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic practice guideline P:28 O:1
• Conservation: PhyloP100: 8.82

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02138195 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of -48, new splice context is: gatgtgcctttcaaattcAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117587738-G-A is Pathogenic according to our data. Variant chr7-117587738-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7112.Status of the report is practice_guideline, 4 stars. Variant chr7-117587738-G-A is described in Lovd as [Pathogenic]. Variant chr7-117587738-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1585-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1585-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

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: 0.00

GnomAD3 exomes AF: 0.0000718 AC: 18 AN: 250846 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 212 AN: 1433950 Hom.: 0 Cov.: 26 AF XY: 0.000136 AC XY: 97 AN XY: 715190

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74410

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 2 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:13 Other:1

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Apr 25, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1585-1G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant. 5/5 splice-tools in Alamut predict that this variant affects the 3' splicing acceptor site and may generate an alternative 3' splicing acceptor site leading to c.1717delG. These predictions were confirmed by minigene and in vivo RNA analysis (Sosnay_2013). This variant is found in 11/120496 control chromosomes at a frequency of 0.0000913, which does not exceed maximal expected frequency of a pathogenic allele (0.0129603). This variant is a commonly known pathogenic variant, and multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -

Mar 03, 2004

American College of Medical Genetics and Genomics (ACMG)

Significance: Pathogenic

Review Status: practice guideline

Collection Method: curation

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 11, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disease-causing CFTR mutation. See www.CFTR2.org for phenotype information. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 11 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs76713772, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with cystic fibrosis, and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). This variant is also known as 1717-1G>A. ClinVar contains an entry for this variant (Variation ID: 7112). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.1585-1G>A(aka 1717-1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1585-1G>A(aka 1717-1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 1 patient 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, PS3_SUP, PM2_SUP, PM3_VSTR -

Jul 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1585-1G>A intronic pathogenic mutation (also known as 1717-1G>A) results from a G to A substitution one nucleotide upstream from coding exon 12 of the CFTR gene. This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). A functional in vitro study reported an absence of normally spliced RNA in expression minigenes transfected into HEK293 cells (Sharma N et al. Hum. Mutat., 2014 Oct;35:1249-59). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has also been reported in the literature as c.1717-1G>A. This variant affects the canonical splice acceptor site of intron 10 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a common pathogenic variant in individuals with cystic fibrosis (CF) (PMID: 2236053, 23974870, 20301428). Functional studies have demonstrated that this variant results in aberrant transcription of the CFTR gene (PMID: 25066652). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0071% (20/282220) and thus is presumed to be rare. Based on the available evidence, the c.1585-1G>A variant is classified as Pathogenic. -

Aug 24, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1585-1G>A variant, also known as c.1717-1G>A, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1585-1G>A variant is listed by the ACMG as part of a panel recommended for routine diagnostic and carrier testing for cystic fibrosis (Watson et al. 2004). The c.1585-1G>A variant is one of the ten most common CFTR variants in persons of northern European descent, accounting for 0.6% of disease and is associated with a classic cystic fibrosis phenotype (Moskowitz et al. 2001). The variant is found in 635/79392 disease-associated alleles in individuals from North America and Europe (Sosnay et al. (2013). Control data are unavailable for this variant, which is reported at a frequency of 0.001395 in the European American cohort of the Exome Sequencing Project. Based on the collective evidence the c.1585-1G>A variant classified as pathogenic for cystic fibrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:10

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1585-1G>A variant (rs76713772), also known as 1717-1G>A, has been reported in patients with the pancreatic insufficient form of cystic fibrosis (Guillermit 1990, Kerem 1990, Ivady 2011, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 7112), is found in the non-Finnish European population with an allele frequency of 0.015% (19/128,796 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 11, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Guillermit H et al. A 3' splice site consensus sequence mutation in the cystic fibrosis gene. Hum Genet. 1990 85(4):450-3. PMID: 2210769 Ivady G et al. Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011 10(3):217-20. PMID: 21296036 Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 87(21):8447-51. PMID: 2236053 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 -

Mar 28, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1585-1G>A pathogenic variant in the CFTR gene is one of the common pathogenic variants associated with cystic fibrosis (Kerem et al., 1990; Hull et al., 1993; Ooi et al., 2012). This splice site variant destroys the canonical splice acceptor site in intron 11. Functional studies show this variant results in skipping of exon 12 with a frameshift that results in a premature termination codon, and the mRNA is not able to generate a stable protein product (Hull et al., 1993; Sharma et al., 2014). Although not present in the homozygous state, the NHLBI Exome Sequencing Project reports that c.1585-1G>A was observed in 12/8600 alleles (0.14%) from individuals of European American background, indicating it may be a rare variant in this population. We interpret c.1585-1G>A as a pathogenic variant. -

Aug 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1585-1G>A (also known as 1717-1G>A) variant disrupts a canonical splice-acceptor site and interferes with normal CFTR mRNA splicing. This variant is associated with cystic fibrosis (CF) (PMIDs: 29261177 (2018), 31036917 (2019), and 34782259 (2021)), and has been reported along with other pathogenic CFTR variants in individuals with classic CF (PMID: 7689009 (1993)), pancreatic insufficiency (PMIDs: 2236053 (1990), 2210769 (1990), 1757966 (1991), and 23974870 (2013)) and in at least one individual with chronic obstructive pulmonary disease (PMID: 34996830 (2022)). Experimental studies have also shown that this variant results in exon 12 skipping and therefore disrupts protein production (PMIDs: 7689009 (1993), 23974870 (2013) and 25066652 (2014)). The frequency of this variant in the general population, 0.0002 (10/50648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:2

Sep 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1585-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, previously described as c.1717-1G>A, is known to be causative for cystic fibrosis (see for example Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227792-G-A). Variants that disrupt the consensus splice acceptor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -

May 20, 2019

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 2
DS_AL_spliceai		0.97		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs76713772; hg19: chr7-117227792;