rs77010898

chr7-117642566-G-Achr7-117642566-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):c.3846G>A(p.Trp1282Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,613,376 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic practice guideline P:32 O:3
• Conservation: PhyloP100: 9.42

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117642566-G-A is Pathogenic according to our data. Variant chr7-117642566-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7129.Status of the report is practice_guideline, 4 stars. Variant chr7-117642566-G-A is described in Lovd as [Pathogenic]. Variant chr7-117642566-G-A is described in Lovd as [Pathogenic]. Variant chr7-117642566-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3846G>A	p.Trp1282Ter	stop_gained	23/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3846G>A	p.Trp1282Ter	stop_gained	23/27	1	NM_000492.4	P2
	ENST00000456270.1	n.65+4785C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000458 AC: 115 AN: 250892 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1461246 Hom.: 1 Cov.: 32 AF XY: 0.000268 AC XY: 195 AN XY: 726928

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00923

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000729

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000959

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32 Other:3

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:15 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2022	The p.W1282* pathogenic mutation (also known as c.3846G>A), located in coding exon 23 of the CFTR gene, results from a G to A substitution at nucleotide position 3846. This changes the amino acid from a tryptophan to a stop codon within coding exon 23. This alteration was originally reported in two individuals with cystic fibrosis, one with p.F508del as the second mutation and the other with an unknown second mutation (Vidaud M et al. Hum Genet. 1990;85(4):446-449). This alteration is also associated with pancreatic insufficiency, elevated sweat chloride levels, and higher rate of Pseudomonas infection (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Of note, this alteration is also known as 3978G>A in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 02, 2023	Criteria applied: PVS1, PS3, PM3_VSTR, PM2_SUP -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 11-16-2013 by Lab or GTR ID 320494. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000492.3(CFTR):c.3846G>A(W1282) 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.3846G>A(W1282) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 30, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 15, 2014	The Trp1282X variant in CFTR has been identified in numerous patients with cystic fibrosis (Viduad 1990, Kerem 1990, Hamosh 1991, Shoshani 1992). This variant is present on the American Board of Medical Genetics CFTR mutation panel (http://www.acmg.net/Pages/ACMG_Activities/stds-2002/cf.htm). This nonsense variant leads to a premature termination codon at position 1282, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Trp1282*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs77010898, gnomAD 0.9%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (CF). It is included in the American College of Medical Genetics (ACMG) panel of CF variants. It is one of the most common causes of cystic fibrosis. (PMID: 2475911, 15371902, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2475911, 15371902, 23974870). This variant is also known as W1282X. ClinVar contains an entry for this variant (Variation ID: 7129). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 18, 2018	The CFTR c.3846G>A (p.Trp1282Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant was first reported by Vidaud et al. (1990) in one patient with cystic fibrosis who was a compound heterozygote for the p.Trp1282Ter variant and the common pathogenic p.Phe508del variant. Shoshani et al. (1992) later reported the p.Trp1282Ter variant on 63 chromosomes from 119 Israeli cystic fibrosis patients from 97 families, establishing the p.Trp1282Ter variant as the most common cystic fibrosis variant in the Ashkenazi Jewish population in Israel. Zielenski et al. (1995) published data from the Cystic Fibrosis Genetic Analysis Consortium showing that the p.Trp1282Ter variant appears in 535 of 43,849 CF chromosomes, with an overall frequency of 1.2%, and is the fifth most common disease-causing mutation in cystic fibrosis. ACMG guidelines published in 2004 recommend the p.Trp1282Ter variant be included in standard cystic fibrosis carrier screening. The variant is reported at a frequency of 0.00897 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Trp1282Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CFTR: PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 29, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 15, 2023	The CFTR c.3846G>A; p.Trp1282Ter variant (rs77010898) is reported in numerous individuals with cystic fibrosis and commonly associated with pancreatic insufficiency (see CFTR database, Kerem 1990, Shoshani 1992). This variant is also reported in ClinVar (Variation ID: 7129). It is observed in the general population with an overall allele frequency of 0.04% (121/282282 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org/ Kerem BS et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8447-51. PMID: 2236053. Shoshani T et al. Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet. 1992 Jan;50(1):222-8. PMID: 1370365. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2018	The W1282X pathogenic variant in the CFTR gene is one of the most common variants associated with classic cystic fibrosis, including pancreatic insufficiency, when found in a homozygous state or when compound heterozygous with another CFTR pathogenic variant (Moskowitz et al., 2008; Kerem et al., 1990). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. W1282X was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The pathogenic variant was not present in the homozygous state within this population. We interpret W1282X as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 30, 2022	- -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 30, 2021	The CFTR c.3846G>A (p.Trp1282*, or W1282X) variant causes the premature termination of CFTR protein synthesis. In the published literature, this variant is associated with severe pancreatic insufficient CF, classic CF, and is the most prevalent CF pathogenic variant in the Ashkenazi Jewish population (PMIDs: 29298718 (2018), 23951356 (2013), 21416780 2010), 1370365 (1992)). The frequency of this variant in the general population, 0.0097 (100/10360 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2018	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 03-06-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 05, 2017

Variant summary: The CFTR c.3846G>A (p.Trp1282X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 46/120654 control chromosomes at a frequency of 0.0003813, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant is a common disease variant reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including CFTR2. Taken together, this variant is classified as pathogenic. -

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

May 12, 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

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 29, 2019

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77010898; hg19: chr7-117282620; COSMIC: COSV99069637;