7-117639961-C-T

Position:

• chr7-117639961-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000492.4(CFTR):​c.3718-2477C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 152,004 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 0.00012 (0 hom., cov: 33)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Pathogenic practice guideline P:27 O:1
• Conservation: PhyloP100: -0.590

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117639961-C-T is Pathogenic according to our data. Variant chr7-117639961-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7166.Status of the report is practice_guideline, 4 stars. Variant chr7-117639961-C-T is described in Lovd as [Pathogenic]. Variant chr7-117639961-C-T is described in Lovd as [Pathogenic]. Variant chr7-117639961-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3718-2477C>T		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3718-2477C>T		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152004 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000479

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152004 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74220

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.000121

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change falls in intron 22 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 may result in an absent or disrupted protein product. This variant is present in population databases (rs75039782, gnomAD 0.3%). This variant has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics panel of CF variants (PMID: 15371902, 23974870, 26631874). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3849+10kbC>T in intron 19. ClinVar contains an entry for this variant (Variation ID: 7166). Studies have shown that this variant results in inclusion of a pseudo-exon and introduces a premature termination codon (PMID: 7521937). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 10 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: PS3, PM2_SUP, PM3_VSTR, PM4, PP4 -
not provided, no classification provided	literature only	GeneReviews	-	- -
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, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 16, 2022	PS3, PM2, PM3_Very Strong, PP3 -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is classified as pathogenic in the context of cystic fibrosis and is associated with non-classic disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) 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, no assertion criteria provided	literature only	OMIM	Jul 03, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The c.3718-2477C>T variant in CFTR (also known as 3849+10kbC>T) has been reported, in the homozygous and compound heterozygous state, in numerous individuals with cystic fibrosis with and without pancreatic insufficiency (selected publications: Abeliovich 1992 PMID: 1384328, Highsmith 1994 PMID: 7521937, Liang 1998 PMID: 9719631, Watson 2004 PMID: 15371902, de Gracia 2005 PMID: 15994263, Duguépéroux 2005 PMID: 15738290, Ooi 2011 PMID: 20923678). It has also been identified in 0.2% (6/3470) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This deep intronic variant was classified as Pathogenic on Mar 17 2017 by the ClinGen-approved CFTR2 expert panel (also pathogenic per practice guideline) (Variation ID 7166). In vitro functional studies have shown that this variant creates a cryptic splice site that causes the creation of a new exon containing an in-frame premature stop codon, the resulting mRNA is predicted to undergo nonsense-mediated decay (Highsmith 1994 PMID: 7521937). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM2_supporting, PM3_Very Strong, PS3. -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PS3,PM3(very strong),PM2 -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	The CFTR c.3718-2477C>T variant (rs75039782), also known as 3717+12191C>T or 3849+10kbC>T, is reported in the literature in individuals affected with pancreatic sufficient cystic fibrosis (Highsmith 1994, McKone 2003, Ooi 2012, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 7166), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site and activating a nearby cryptic acceptor splice site. Functional assays show that this leads to the abnormal inclusion of intronic sequence, in the form of a new 84bp exon in the CFTR mRNA (Highsmith 1994). The new exon also includes an in-frame termination codon, which is predicted to result in a truncated protein and or absent transcript. Based on available information, this variant is considered to be pathogenic. References: Highsmith WE et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med.1994 331(15):974-80. PMID: 7521937 McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 361(9370):1671-6. PMID: 12767731 Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. PMID: 22658665 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 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	CFTR: PM3:Very Strong, PM2, PS3:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2022	This variant has been reported in affected individuals with Cystic Fibrosis, congenital bilateral absence of the vas deferens, and CFTR related diseases (PMIDs: 23974870 (2013), 24440181 (2014), 28603918 (2017), 28863137 (2017), and 29261177 (2018)). This variant has also been reported to result in aberrant CFTR splicing, specifically the inclusion of an 84-bp pseudo exon containing a premature stop codon (PMIDs: 24440181 (2014) and 28863137 (2017)).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 09, 2023	The CFTR c.3718-2477C>T variant (also known as 3849+10kbC>T, c.3717+12191C>T) has been reported in the published literature to induce aberrant CFTR splicing, specifically the inclusion of an 84-bp pseudo exon containing a premature stop codon that reduced amount of normal CFTR mRNA synthesized (PMIDs: 7521937 (1994), 18456578 (2008), 28863137 (2017)). In addition, this variant has been reported in individuals with cystic fibrosis and CFTR-related disorders, typically associated with mild clinical manifestations and pancreatic sufficiency (PMIDs: 7521937 (1994), 8533846 (1995), 12767731 (2003), 15738290 (2005), 28603918 (2017)). This variant is a known CF mutation (PMID: 32404922 (2020), CFTR2 (http://www.cftr2.org/)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 07, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 31, 2023	The CFTR c.3718-2477C>T variant is predicted to interfere with splicing. This variant is also referred to as 3849+10kbC>T or c.3717+12191C>T. This variant has previously been reported to be causative in multiple cystic fibrosis patients with a mild phenotype (Highsmith et al. 1994. PubMed ID: 7521937; McKone et al. 2003. PubMed ID: 12767731; Duguépéroux et al. 2005. PubMed ID: 15738290; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org) and is included in the American College Medical Genetics (ACMG) panel of CF variants (Watson et al. 2004. PubMed ID: 15371902; Deignan JL et al. 2023. PubMed ID: 37310422). We classify this variant as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 13, 2017

Variant summary: The CFTR c.3718-2477C>T variant involves the alteration of a non-conserved deep intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict a significant impact on splicing. Functional analysis confirms that this variant is associated with an abnormally spliced product (Highsmith_1994). This variant was found in 2/30924 control chromosomes (gnomAD) at a frequency of 0.0000647, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in multiple CF patients with a mild phenotype, including 3 homozygotes (Duguproux_2005, Gilbert_1995) and was included in the ACMG CFTR list (Watson_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Nov 01, 2021

- -

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

Oct 31, 2018

- -

Cystic fibrosis;C5924204: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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs75039782; hg19: chr7-117280015;