7-117611555-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.3140-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,312,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CFTR
NM_000492.4 intron

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:24

Conservation

PhyloP100: -0.133

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-117611555-A-G is Pathogenic according to our data. Variant chr7-117611555-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 35864.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611555-A-G is described in Lovd as [Pathogenic]. Variant chr7-117611555-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3140-26A>G		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3140-26A>G		intron_variant		1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4674T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000423

AC:

AN:

236632

Hom.:

AF XY:

0.0000550

AC XY:

AN XY:

127380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000904

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:

0.0000668

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

125

AN:

1160806

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

591218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000721

Gnomad4 AMR exome

AF:

0.0000695

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000506

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.0000791

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.3140-26A>G(aka 3272-26A>G) is classified as pathogenic and is a non-classic variant in the context of cystic fibrosis. Sources cited for classification include the following: PMID: 10425036 and 23974870. Classification of NM_000492.3(CFTR):c.3140-26A>G(aka 3272-26A>G) 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, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 20, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change falls in intron 19 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs76151804, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 17481968, 23974870). It has also been observed to segregate with disease in related individuals. This variant is also known as 3272-26A>G. ClinVar contains an entry for this variant (Variation ID: 35864). Studies have shown that this variant alters CFTR gene expression (PMID: 12397022, 23974870). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	Ambry Genetics	Mar 31, 2022	The c.3140-26A>G intronic pathogenic mutation (also known as 3272-26A>G) results from an A to G substitution 26 nucleotides upstream from coding exon 20 in the CFTR gene. This alteration has been shown to alter splicing and add 25 nucleotides to the final transcript, causing a premature translational stop codon (Beck S et al. Hum. Mutat., 1999;14:133-44). Another study demonstrated this pathogenic mutation, when in combination with p.F508del, decreased the amount of normal CFTR mRNA to 8.2% of total CFTR mRNA (Ramalho AS et al. Am. J. Respir. Cell Mol. Biol., 2002 Nov;27:619-27). In a cohort of 60 individuals with cystic fibrosis, this alteration was associated with a later presentation of disease, a reduced risk of pancreatic insufficiency, and better lung function (Amaral MD et al. J. Med. Genet., 2001 Nov;38:777-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 10425036) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 35864; PMID: 25910067; PMID: 25122143; PMID: 24243928; PMID: 23810505; PMID: 15365999; PMID: 28603918) - PS4. The variant is present at low allele frequencies population databases (rs76151804 – gnomAD 0.0004850%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.3140-26A>G was detected in trans with a pathogenic variant (PMID: 23810505; PMID: 28603918; PMID: 10425036) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 20, 2023	- -

not provided

Pathogenic:8

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	Eurofins Ntd Llc (ga)	Apr 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CFTR c.3140-26A>G variant has been reported in several compound heterozygous cystic fibrosis (CF) patients who also carried the p.F508del variant or another pathogenic CFTR variant (Pereira_2019_ PMID: 30996306; Beck_1999_PMID:10425036; Ramalho_2002_PMID:12397022; Storm_2007_PMID:17481968). This variant has been reported to be associated with a milder CF phenotype (Beck_1999_PMID:10425036). The variant was identified in dbSNP (ID: rs76151804) and ClinVar (classified as pathogenic by Invitae, EGL Genetics and seven other submitters). The variant was identified in control databases in 13 of 268026 chromosomes at a frequency of 0.0000485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 4 of 34026 chromosomes (freq: 0.000118), European (non-Finnish) in 8 of 120280 chromosomes (freq: 0.000067) and African in 1 of 24118 chromosomes (freq: 0.000041), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), other, or South Asian populations. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. Multiple functional studies have confirmed this aberrant splicing and have determined that this variant extends exon 20 by 25 base pairs, which causes a frameshift leading to a premature stop codon (Sanz_2017_PMID: 28863137; Beck_1999_PMID:10425036; Ramalho_2002_PMID: 12397022). Compared to wild type, patient cells with this variant only have 5% normal CFTR mRNA (Ramalho_2002_PMID: 12397022). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 21, 2023	The CFTR c.3140-26A>G (also known as 3272-26A>G) variant leads to the creation of an alternative splice acceptor site that competes with the normal splice site during RNA processing. The use of this alternative splice site results in the occurrence of an alternatively spliced mRNA with 25 extra nucleotides from intron 19 and a premature stop codon soon thereafter (PMID: 10425036 (1999)). In the published literature, this variant in compound heterozygous and homozygous state is associated with mild CF phenotype and pancreatic sufficiency (PMIDs: 34782259 (2021), 33855558 (2020), 22658665 (2012), 17481968 (2007), 11732487 (2001), 10425036 (1999), 7542347 (1995), 1379210 (1992)). The frequency of this variant in the general population, 0.00012 (4/34026 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, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 12, 2021	PS3, PM3, PM2, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 14, 2019

The CFTR c.3140-26A>G variant (rs76151804), also known as 3272-26A>G, is reported in the literature in multiple patients diagnosed with cystic fibrosis (CF), typically with pancreatic sufficiency (Fanen 1992, Beck 1999, Amaral 2001, Ramalho 2002, Sosnay 2013, CFTR2 database), and in individuals with pancreatitis (Ooi 2012) or congenital bilateral absence of the vas deferens (Steiner 2011). Many affected individuals with this variant also carry a second pathogenic CFTR variant (Fanen 1992, Beck 1999, Ramalho 2002, Steiner 2011). The c.3140-26A>G variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 35864), and it is found in the general population with an overall allele frequency of 0.005% (13/268026 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a novel cryptic acceptor splice site. Messenger RNA analysis reveals that the variant causes aberrant splicing of the CFTR transcript, leading to the inclusion of 25 additional nucleotides of intron 17a (Beck 1999). This results in a premature stop codon at exon 17b, which results in the degradation of the majority of the aberrant CFTR transcript and only 4-5 percent of normal CFTR protein production compared to healthy individuals (Ramalho 2002, Sosnay 2013). Based on available evidence, the c.3140-26A>G variant is classified as pathogenic. References: CFTR2 Database: http://cftr2.org/ Amaral M et al. Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study. J Med Genet. 2001; 38(11):777-83. Beck S et al. Cystic fibrosis patients with the 3272-26A-->G mutation have mild disease, leaky alternative mRNA splicing, and CFTR protein at the cell membrane. Hum Mutat. 1999; 14(2):133-44. Fanen P et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992; 13(3):770-6. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Ramalho A et al. Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Am J Respir Cell Mol Biol. 2002; 27(5):619-27. 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. Steiner B et al Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. -

Cystic fibrosis;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

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

Aug 04, 2021

- -

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

Oct 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

Cadd

Uncertain

Dann

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: 1

DS_AL_spliceai

0.42

Position offset: 26

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