7-117531115-G-T

Position:

• chr7-117531115-G-T

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.489+1G>T variant causes a splice donor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic practice guideline P:29 O:1
• Conservation: PhyloP100: 9.52

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 0.048390727 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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.489+1G>T		splice_donor_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.489+1G>T		splice_donor_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152116 Hom.: 0 Cov.: 32

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

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

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

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:29 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2024	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. -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Oct 15, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	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 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2021	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. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 28, 2019	- -

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CFTR: PM3:Very Strong, PVS1:Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2023	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. -
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	Dec 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2023	- -

CFTR-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Aug 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 29, 2024	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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jul 28, 2022

- -

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 21, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2024

- -

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
MutationTaster	Benign	1.0	D;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

Other links and lift over

dbSNP: rs78756941; hg19: chr7-117171169;