7-117611555-A-G

Variant names:

• chr7-117611555-A-G
• rs76151804
• NM_000492.4:c.3140-26A>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic reviewed by expert panel P:24
• Conservation: PhyloP100: -0.133

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]

ENSG00000083622 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3140-26A>G		intron_variant	Intron 19 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3140-26A>G		intron_variant	Intron 19 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152118 Hom.: 0 Cov.: 31

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: 10 AN: 236632 Hom.: 0 AF XY: 0.0000550 AC XY: 7 AN XY: 127380

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.: 0 Cov.: 16 AF XY: 0.000105 AC XY: 62 AN XY: 591218

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: 9 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74298

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.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:11

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 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.3140-26A>G variant (rs76151804; ClinVar Variation ID: 35864), also known as 3272-26A>G, is reported in the literature in multiple patients diagnosed with cystic fibrosis (CF), typically with pancreatic sufficiency (Amaral 2001, Beck 1999, Fanen 1992, 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 (Beck 1999, Fanen 1992, Ramalho 2002, Steiner 2011). This variant is found in the general population with an overall allele frequency of 0.005% (13/268026 alleles) in the Genome Aggregation Database (v2.1.1). This is an intronic variant and 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 information, this variant is considered to be pathogenic. References: CFTR2 Database: http://cftr2.org/ Amaral MD 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 Nov;38(11):777-83. PMID: 11732487. 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. PMID: 10425036. 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 Jul;13(3):770-6. PMID: 1379210. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. Ramalho AS 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 Nov;27(5):619-27. PMID: 12397022. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. PMID: 21520337. -

Mar 31, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 20, 2023

Institute of Human Genetics, University of Leipzig Medical Center

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 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. -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2025

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.3140-26A>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Beck_1999). The variant allele was found at a frequency of 4.2e-05 in 236636 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (4.2e-05 vs 0.013), allowing no conclusion about variant significance. c.3140-26A>G has been reported in the literature in multiple individuals affected with Non-Classic Cystic Fibrosis (e.g., Fanen_1992, Cheadle_1993, Dork_1994, Bienvenu_1995, Cuppens_1993, Alonso_2007, Feldmann_2003, Beck_1999, Goldman_2001, Claustres_2000). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Beck_1999). The following publications have been ascertained in the context of this evaluation (PMID: 7508414, 1379210, 17331079, 10923036, 12955726, 7525450, 10425036, 8592345, 11732487, 7505689, 11168023). ClinVar contains an entry for this variant (Variation ID: 35864). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Feb 20, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:8

Apr 27, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 laboratory’s criteria to be classified as pathogenic. -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:1

Mar 17, 2017

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

- -

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

Apr 17, 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 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Uncertain	25
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

Other links and lift over

dbSNP: rs76151804; hg19: chr7-117251609; COSMIC: COSV50081323; COSMIC: COSV50081323;