7-117590442-A-G

Variant names:

• chr7-117590442-A-G
• rs397508298
• NM_000492.4:c.1766+3A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1766+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000025 in 1,599,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Scores: Splicing: ADA: 0.9832
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 5.31
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117590442-A-G is Pathogenic according to our data. Variant chr7-117590442-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 53379.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1766+3A>G		splice_region intron	N/A	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1766+3A>G		splice_region intron	N/A	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1766+3A>G		splice_region intron	N/A	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1676+3A>G		splice_region intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447328 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719824

African (AFR) AF: 0.00 AC: 0 AN: 33152

American (AMR) AF: 0.00 AC: 0 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25556

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102154

Other (OTH) AF: 0.00 AC: 0 AN: 59508

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:9

Dec 30, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1766+3A>G (also known as 1898+3A>G) intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 13 in the CFTR gene. This mutation has been reported in cystic fibrosis patients from Italy, Spain, and Finland (Cremonesi L, Hum. Mutat. 1992 ; 1(4):314-9; Casals T, Hum. Genet. 1997 Dec; 101(3):365-70; Kinnunen S, J. Cyst. Fibros. 2005 Dec; 4(4):233-7). This mutation results in full exon skipping resulting in zero correctly spliced RNA (Dujardin G, J. Cyst. Fibros. 2011 May; 10(3):212-6) and it is associated with elevated sweat chloride levels, decreased lung function, and pancreatic sufficiency (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 28, 2015). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Sep 06, 2022

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, 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.1766+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: 3 predict the variant weakens a 5' donor site. At least one publication reports experimental evidence confirming that this variant affects mRNA splicing, and causes exon 12 skipping in a mini-gene system (Dujardin_2011). The variant allele was found at a frequency of 2.5e-06 in 1592600 control chromosomes in the gnomAD database (v4.1 dataset). c.1766+3A>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Dujardin_2011, Sosnay_2013). 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: 23974870, 21317048). ClinVar contains an entry for this variant (Variation ID: 53379). Based on the evidence outlined above, the variant was classified as pathogenic.

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 04, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individuals with cystic fibrosis (PMID: 15480987, 18178635). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CFTR protein in which other variant(s) (p.Asp579Gly) have been determined to be pathogenic (PMID: 7544319, 15463898, 26494713, 27738188, 27812499). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 13, but is expected to preserve the integrity of the reading-frame (PMID: 21317048, 32935393). ClinVar contains an entry for this variant (Variation ID: 53379). This variant is also known as 1898+3A>G. This variant is not present in population databases (gnomAD no frequency). 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.

Jun 27, 2019

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not provided Pathogenic:2

Aug 12, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1766+3A>G variant (rs397508298), also reported as c.1898+3A>G, is reported in the literature as heterozygous and homozygous in individuals affected with cystic fibrosis (Casals 1997, Cremonsei 1992, Hirtz 2004, Stanke 2008, Sosnay 2013). Functional analyses of the variant found it resulted in the skipping of exon 12 (Dujardin 2011, Fernandez Alanis 2012). This variant is reported as pathogenic by an expert panel ClinVar (Variation ID: 53379) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. PMID: 9439669. Cremonesi L et al. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat. 1992;1(4):314-9. PMID: 1284538. Dujardin G et al. Splicing defects in the CFTR gene: minigene analysis of two mutations, 1811+1G>C and 1898+3A>G. J Cyst Fibros. 2011 May;10(3):212-6. PMID: 21317048. Fernandez Alanis E et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. PMID: 22362925. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004 Oct;127(4):1085-95. PMID: 15480987. Stanke F et al. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans. J Med Genet. 2008 Jan;45(1):47-54. PMID: 18178635. 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.

May 23, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR-related disorder Pathogenic:1

Sep 04, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 02, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Benign	0.92
PhyloP100		5.3
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
Splicevardb		3.0
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: -3

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

Other links and lift over

dbSNP: rs397508298; hg19: chr7-117230496;