rs121908761

chr7-117611717-C-Achr7-117611717-C-Gchr7-117611717-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000492.4(CFTR):c.3276C>A(p.Tyr1092Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21

Conservation

PhyloP100: 0.784

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 7-117611717-C-A is Pathogenic according to our data. Variant chr7-117611717-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 38728.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117611717-C-A is described in Lovd as [Pathogenic]. Variant chr7-117611717-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3276C>A	p.Tyr1092Ter	stop_gained	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3276C>A	p.Tyr1092Ter	stop_gained	20/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4512G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251144

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461426

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000515

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000492.3(CFTR):c.3276C>A(Y1092) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 18456578, 1284534 and 23974870. Classification of NM_000492.3(CFTR):c.3276C>A(Y1092) 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, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Tyr1092*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with cystic fibrosis and chronic pancreatitis. A second, pathogenic, CFTR variant was not reported in this individual (PMID: 10950058, 12815607, 15480987, 18456578, 21416780, 23974870, 24586523, 25910067). ClinVar contains an entry for this variant (Variation ID: 38728). 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, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2021	The p.Y1092* pathogenic mutation (also known as c.3276C>A), located in coding exon 20 of the CFTR gene, results from a C to A substitution at nucleotide position 3276. This changes the amino acid from a tyrosine to a stop codon within coding exon 20. This pathogenic mutation was first described in an individual with pancreatic insufficient cystic fibrosis in conjunction with p.F508del (Bozon D et al. Hum. Mutat., 1994;3:330-2). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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	Johns Hopkins Genomics, Johns Hopkins University	Jun 03, 2021	- -

not provided

Pathogenic:7

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	GeneDx	Feb 28, 2018	The Y1092X pathogenic variant in the CFTR gene has been reported previously as a cystic fibrosis-causing variant, accounting for approximately 0.2% of all cystic fibrosis mutant alleles (Tsui, 1992; Sosnay et al., 2013). The Y1092X variant has also been implicated in chronic pancreatitis and pancreatic insufficiency (Ockenga et al., 2000; Ooi and Durie, 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y1092X variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). We interpret Y1092X as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2023	The CFTR c.3276C>A; p.Tyr1092Ter variant (rs121908761) has been reported in the medical literature in several individuals with pancreatic insufficient cystic fibrosis (Castellani 2008, De Braekeleer 1998, Sosnay 2013). The variant is reported in ClinVar (Variation ID: 38728) and is reported in the general population with an overall allele frequency of 0.0018% (5/282,504 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: Castellani C et al. Consensus on the Use and Interpretation of Cystic Fibrosis Mutation Analysis in Clinical Practice. J Cyst Fibros. 2008 May;7(3):179-96. PMID: 18456578. De Braekeleer M et al. Phenotypic Variability in Five Cystic Fibrosis Patients Compound Heterozygous for the Y1092X Mutation. Hum Hered. May-Jun 1998;48(3):158-62. PMID: 9618063. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2018	- -

CFTR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 02, 2024	The CFTR c.3276C>A variant is predicted to result in premature protein termination (p.Tyr1092). This variant has been reported in the compound heterozygous state in multiple individuals with cystic fibrosis (Bozon et al. 1994. PubMed ID: 7517268; Scotet et al. 2003. PubMed ID: 12815607; Sosnay et al. 2013. PubMed ID: 23974870; Ziętkiewicz et al. 2014. PubMed ID: 24586523; Lucarelli et al. 2015. PubMed ID: 25910067; Raraigh et al. 2022. PubMed ID: 34782259) and has been observed to co-segregate with disease in a large French Canadian family (De Braekeleer et al. 1998. PubMed ID: 9618063). It has also been reported as a single heterozygous variant in a patient with chronic pancreatitis (Ockenga et al. 2000. PubMed ID: 10950058). A different nucleotide substitution with the same predicted effect (c.3276C>G, p.Tyr1092) has also been reported in multiple individuals with cystic fibrosis (Schrijver et al. 2005. PubMed ID: 16049310; Raraigh et al. 2022. PubMed ID: 34782259) and an absence of chloride channel function has been noted in in vitro studies of biopsied tissue samples and primary cell cultures from patients heterozygous for both the p.Phe508del and p.Tyr1092* variants (Hirtz et al. 2004. PubMed ID: 15480987; Awatade et al. 2015. PubMed ID: 26137539). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 13, 2018

Variant summary: The variant CFTR c.3276C>A (p.Tyr1092X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 245972 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Bozon_1994, DeBraekeleer_1998, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

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

Jan 05, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;A

Vest4

0.93

ClinPred

0.90

GERP RS

2.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over