7-117531115-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000492.4(CFTR):​c.489+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,606,712 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 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CFTR
NM_000492.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic practice guideline P:29O:1

Conservation

PhyloP100: 9.52
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 0.0486158 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 7-117531115-G-T is Pathogenic according to our data. Variant chr7-117531115-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 38799.Status of the report is practice_guideline, 4 stars. Variant chr7-117531115-G-T is described in Lovd as [Pathogenic]. Variant chr7-117531115-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.489+1G>T splice_donor_variant, intron_variant Intron 4 of 26 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.489+1G>T splice_donor_variant, intron_variant Intron 4 of 26 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000773
AC:
19
AN:
245706
Hom.:
0
AF XY:
0.000106
AC XY:
14
AN XY:
132670
show subpopulations
Gnomad AFR exome
AF:
0.0000626
Gnomad AMR exome
AF:
0.00
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:
0.000163
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000205
AC:
298
AN:
1454596
Hom.:
0
Cov.:
29
AF XY:
0.000221
AC XY:
160
AN XY:
723762
show subpopulations
Gnomad4 AFR exome
AF:
0.0000899
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:
0.000258
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.0000907
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:29Other:1
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:14Other:1
Nov 05, 2018
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dec 30, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.489+1G>T intronic pathogenic mutation (also known as 621+1G>T) results from a G to T substitution one nucleotide after coding exon 4 of the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. Analysis of mRNA isolated from nasal epithelial cells of one proband showed that the mutation results in skipping of partial and full exon 4, leading to in-frame transcripts (Zielenski J et al. Hum. Mol. Genet., 1993 Jun;2:683-7). The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been described in the homozygous state in 5 individuals with pancreatic insufficient cystic fibrosis (CF) (De Braekeleer M et al. J. Med. Genet., 1997 Sep;34:788-9) and has also been identified in a compound heterozygous state with another CFTR mutation in individuals with CF (Zielenski J et al. Hum. Mol. Genet., 1993 Jun;2:683-7; Petrova NV et al. Genes (Basel) 2020 05;11(5)). In addition, this mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (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. -

Aug 28, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 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 (rs78756941, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 38799). 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. -

Jan 29, 2018
CFTR-France
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Mar 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CFTR c.489+1G>T variant (rs78756941), also known as 621+1G>T, has been reported in patients diagnosed with the pancreatic insufficient form of cystic fibrosis (Zielenski 1991, Sheridan 2011, Ooi 2012, Sosnay 2013). This variant is classified as pathogenic by an expert panel in ClinVar (Variation ID: 38799) and is found in the non-Finnish European population with an allele frequency of 0.01 (18/125670 alleles) in the Genome Aggregation Database. Computational algorithms (Alamut v.2.11) predict the loss of the canonical splice donor, leading to the production of aberrant RNA transcripts (Sheridan 2011). Based on the above information, this variant is classified as pathogenic. References: Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. PMID: 20923678. Sheridan M et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011; 48(4):235-41. 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. Zielenski J et al. Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1991 May;10(1):229-35. PMID: 1710599. -

Mar 03, 2004
American College of Medical Genetics and Genomics (ACMG)
Significance: Pathogenic
Review Status: practice guideline
Collection Method: curation

- -

Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 12, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000492.3(CFTR):c.489+1G>T(aka 621+1G>T) 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.489+1G>T(aka 621+1G>T) 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. -

Oct 15, 2014
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 05, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CFTR c.489+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by exon skipping (Aissat_2013). The variant allele was found at a frequency of 7.7e-05 in 245706 control chromosomes. c.489+1G>has been detected in hundreds of CF patients in the literature and is a known common disease causing mutation (example, Sosnay_2013, McKone_2003).These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12767731, 23974870, 23420618). ClinVar contains an entry for this variant (Variation ID: 38799). Based on the evidence outlined above, the variant was classified as pathogenic. -

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 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, PM2_SUP, PM3_VSTR, PP4 -

Mar 17, 2017
CFTR2
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: research

- -

May 12, 2016
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

not provided Pathogenic:8
Dec 06, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CFTR: PM3:Very Strong, PVS1:Strong, PM2 -

Jul 16, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 21, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CFTR c.489+1G>T variant disrupts a canonical splice-donor site and interferes with normal CFTR mRNA splicing. This variant has been reported in the published literature along with other CF variants in individuals with cystic fibrosis and is often associated with pancreatic insufficiency (PMID: 1710599 (1991), 9321772 (1997), 9618063 (1998), 23974870 (2013), 32429104 (2020)). This variant has also been reported in individuals with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 16840743 (2006), 22020151 (2012), CFTR-France (https://cftr.iurc.montp.inserm.fr/)). This variant is shown to result in alternative splicing producing two aberrantly spliced transcripts (PMID: 21097845 (2011)). The frequency of this variant in the general population, 0.00014 (18/125670 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 16, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 07, 2018
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.489+1G>T (also reported as 621+1G>T) splice site variant is a well-described pathogenic variant reported in association with cystic fibrosis and other CFTR-related disorders (for examples see Zielenski et al., 1991; Amato et al., 2012, Wilschanski et al., 2006). This pathogenic variant destroys the canonical splice donor site in intron 4 results in abnormal gene splicing (Castellani et al., 2008). We interpret c.489+1G>T as a pathogenic variant. -

CFTR-related disorder Pathogenic:3
Aug 28, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 29, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CFTR c.489+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This splicing variant, also referred to as 621+1G>T in the literature, is a documented cystic fibrosis pathogenic variant (Sosnay et al. 2013. PubMed ID: 23974870). This variant is one of the most common pathogenic variants in CFTR (Watson et al. 2004. PubMed ID: 15371902). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor 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
-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary pancreatitis Pathogenic:1
Jul 28, 2022
MGZ Medical Genetics Center
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
Mar 10, 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 16, 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
0.39
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.84
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.84
Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78756941; hg19: chr7-117171169; API