rs75096551

chr7-117606754-G-Achr7-117606754-G-Cchr7-117606754-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):c.2988+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000662 in 1,525,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic practice guideline P:29 O:1
• Conservation: PhyloP100: 9.25

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017780779 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of 24, new splice context is: taaGTatgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117606754-G-A is Pathogenic according to our data. Variant chr7-117606754-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7224.Status of the report is practice_guideline, 4 stars. Variant chr7-117606754-G-A is described in Lovd as [Pathogenic]. Variant chr7-117606754-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2988+1G>A		splice_donor_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2988+1G>A		splice_donor_variant		1	NM_000492.4	P2
	ENST00000456270.1	n.178-1765C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 42 AN: 151744 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00102

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251006 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135684

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0000579

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000415 AC: 57 AN: 1373366 Hom.: 0 Cov.: 23 AF XY: 0.0000378 AC XY: 26 AN XY: 688738

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.69e-7

Gnomad4 OTH exome AF: 0.000191

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151862 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74208

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000604 Hom.: 0

Bravo AF: 0.000374

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:15 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000492.3(CFTR):c.2988+1G>A(aka 3120+1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.2988+1G>A(aka 3120+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 20, 2021	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderate, PM3 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change affects a donor splice site in intron 18 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs75096551, gnomAD 0.1%). Disruption of this splice site has been observed in individuals with cystic fibrosis, and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). This variant is also known as 3120+1G>A. ClinVar contains an entry for this variant (Variation ID: 7224). 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, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2022	The c.2988+1G>A pathogenic mutation (also known as 3120+1G>A in published literature), is located one nucleotide after coding exon 18 of the CFTR gene. This is one of the most common pathogenic mutations in African American individuals with cystic fibrosis (CF) (Zampoli On Behalf Of The Msac M. S. Afr. Med. J., 2018 Dec;109:16-19). In one study, this mutation was identified in ten affected African American individuals with pancreatic insufficiency (PI) and elevated sweat chloride levels (Macek M Am. J. Hum. Genet. 1997 May;60(5):1122-7). This pathogenic mutation was further described in four African American individuals, one who was homozygous and three compound heterozygous with another mutation. All individuals demonstrated compromised lung function, elevated sweat chloride levels, and PI (Carles S et al. J. Med. Genet. 1996 Sep;33(9):802-4). A functional in vitro study of splice site alterations in CFTR noted this mutation generated no detectable CFTR protein (Sharma N et al Hum. Mutat. 2014 Oct;35(10):1249-59). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. -

not provided Pathogenic:9

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	Revvity Omics, Revvity	Jun 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2023	The CFTR c.2988+1G>A variant (rs75096551), also known as 3120+1G>A, is reported in patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Masekela 2013, Wilschanski 1995), and is associated with elevated sweat levels and pancreatic insufficiency (Masekela 2013, Ooi 2012, Sosnay 2013, see CFTR2 database). This variant is reported in ClinVar (Variation ID: 7224), and is found in the general population with an overall allele frequency of 0.01% (33/282364 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 18, which is likely to negatively impact gene function. Functional characterization indicates that exon 18 is skipped in the CFTR mRNA, and results in the absence of CFTR protein (Sharma 2014). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database link: https://cftr2.org/ Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010; 62(6):546-52. PMID: 21416780 Masekela R et al. Phenotypic expression of the 3120+1G>A mutation in non-Caucasian children with cystic fibrosis in South Africa. J Cyst Fibros. 2013; 12(4):363-6. PMID: 23206872 Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. PMID: 22658665 Sharma N et al. Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions. Hum Mutat. 2014; 35(10):1249-59. PMID: 25066652 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 Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995; 127(5):705-10. PMID: 7472820 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 11, 2020	The pathogenic c.2988+1G>A variant (also known as 3120+1G>A) is located in a canonical splice-donor site and interferes with/prevents normal CFTR mRNA splicing (PMID: 25066652 (2014)). It is a known CF pathogenic variant associated with pancreatic insufficiency, and has been reported in individuals affected with CF in the published literature (PMIDs: 9683582 (1998), 9950364 (1999), 23206872 (2013), and 23974870 (2013)). -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

CFTR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 23, 2023	The CFTR c.2988+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has previously been reported to be causative for cystic fibrosis (Wilschanski et al. 1995. PubMed ID: 7472820; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117246808-G-A). Variants that disrupt the consensus splice donor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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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

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 23, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs75096551; hg19: chr7-117246808;