7-117590444-G-T

Position:

chr7-117590444-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000492.4(CFTR):c.1766+5G>T variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000375 in 1,598,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CFTR
NM_000492.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.5251

Clinical Significance

Pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 3.78

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]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117590444-G-T is Pathogenic according to our data. Variant chr7-117590444-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 48685.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117590444-G-T is described in Lovd as [Pathogenic]. Variant chr7-117590444-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1766+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1766+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249012

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

134960

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1446438

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719434

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000764

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2017	The c.1766+5G>T (NM_000492.3 c.1766+5G>T) variant in CFTR has been reported in 1 homozygous and 3 compound heterozygous Asian individuals with clinical features of cystic fibrosis (Zielenski 1995, Leung 2016, Shen 2016). This variant has be en identified in 0.023% (2/8,562) of East Asian chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908796). This variant is located in the 3' splice region. Computational tools suggest a possib le impact to splicing consistent with the +5 position being predominantly a G nu cleotide. In summary, the clinical significance of the c.1766+5G>T variant is li kely pathogenic based upon biallelic case observations, suggestive splicing impa ct and low frequency in the general population. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 16, 2019	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2016	Variant summary: The CFTR c.1766+5G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 4/5 splicing algorithms predict the weakening or elimination of the splice donor site of exon 13. This prediction is confirmed by cDNA studies performed on RNA isolated from a homozygous patient, showing >95% of transcripts lacking exon 13. This variant was found in 2/119622 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). c.1766+5G>T has been cited in numerous CF patients reported in the literature in both compound heterozygous and homozygous states. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 20, 2015	The c.1766+5G>T intronic pathogenic mutation results from a G to T substitution 5 nucleotides after coding exon 13 in the CFTR gene. This mutation is also known as c.1898+5G>T in published literature. One study identified a CF patient with high sweat levels, respiratory complications and pancreatic insufficiency who carried this mutation in trans with a complex allele (Alper OM et al J Formos Med Assoc. 2003;102(5):287-291). One CF review article indicates that this mutation might account for almost 30% of carrier alleles in the Chinese/Taiwanese population, keeping in mind the small sample sizes (Zielenski et al Annu Rev Genet. 1995; 29:777-807). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native donor splice site. In-vitro functional studies indicate an alternate transcript is formed 77-80% of the time due to exon skipping and an in-frame deletion of exon 12 (Raynal et al Hum Mutat 2013; 34(5):774-784). Based on the supporting evidence, c.1766+5G>T is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Urology, First Affiliated Hospital of Nanjing Medical University	Dec 25, 2023	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change falls in intron 13 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs121908796, gnomAD 0.04%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 7543385, 10925568, 12874665, 18456578). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of East Asian ancestry (PMID: 18456578). This variant is also known as c.1898+5G>T. ClinVar contains an entry for this variant (Variation ID: 48685). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 7543385, 23381846). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23089694, 8213163, 25580864, 16202790, 7543385, 23381846, 12874665 and 18456578. Classification of NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is based on the following criteria: This variant 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. -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	The CFTR c.1766+5G>T variant (rs121908796), also known as 1898+5G>T, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with cystic fibrosis, and is a common variant in East Asian patients (Chen 2012, Liu 2015, Shen 2016, Sontag 2005, Xu 2017). This variant is reported in ClinVar (Variation ID: 48685), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. In vitro functional assays show that this variant results in skipping of exon 12 (Raynal 2013). Based on available information, this variant is considered to be pathogenic. References: Chen CH et al. Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis. J Formos Med Assoc. 2012;111(10):580-583. PMID: 23089694. Liu Y et al. Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology. 2015;20(2):312-318. PMID: 25580864. Raynal C et al. A classification model relative to splicing for variants of unknown clinical significance: application to the CFTR gene. Hum Mutat. 2013;34(5):774-784. PMID: 23381846. Shen Y et al. Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016;171:269-76.e1. PMID: 26826884. Sontag MK et al. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr. 2005;147(3 Suppl):S83-S88. PMID: 16202790. Xu J et al. Four case reports of Chinese cystic fibrosis patients and literature review. Pediatr Pulmonol. 2017;52(8):1020-1028. PMID: 28608624. -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2023

The CFTR c.1766+5G>T variant is predicted to interfere with splicing. This variant, also referred to as c.1898+5G>A using legacy nomenclature, has been reported in the homozygous and compound heterozygous state in patients with cystic fibrosis (Zielenski et al 1995. PubMed ID: 7543385; Castellani C et al 2008. PubMed ID: 18456578; Shen Y et al 2020. PubMed ID: 32761997 ). Another substitution at this same nucleotide position, c.1766+5G>A, has also been reported as causative for cystic fibrosis (des Georges et al 2004. PubMed ID: 15698946; Raynal C et al 2013. PubMed ID: 23381846). Both variants have been reported to result in exon 12 skipping due to alteration of splicing at the exon 12/intron 12 boundary region (Zielenski et al 1995. PubMed ID: 7543385; Raynal C et al 2013. PubMed ID: 23381846). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117230498-G-T). This variant is interpreted as pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.67

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.69

Position offset: -5

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over