rs374705585

Positions:

chr7-117667091-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000492.4(CFTR):c.4426C>T(p.Gln1476*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000204 in 1,613,752 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17U:1

Conservation

PhyloP100: 7.17

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:

CFTR (HGNC:):

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00383 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117667091-C-T is Pathogenic according to our data. Variant chr7-117667091-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117667091-C-T is described in Lovd as [Pathogenic]. Variant chr7-117667091-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-117667091-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4426C>T	p.Gln1476*	stop_gained	27/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.4426C>T	p.Gln1476*	stop_gained	27/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250874

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461594

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000130

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2017	Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely pathogenic truncating variants downstream of this position have been reported in literature, ClinVar and our laboratory and it is outside of some of the commonly known domains (transmembrane domain, ATPase domain and regulator domain) (InterPro). There are no functional studies for this variant as well. Mutation taster predicts a damaging outcome for this variant. This variant was found in 3/120070 control chromosomes including ExAC at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant was found in at least 5 CF patients, 5 CBAVD patients, 3 ICP patients and 3 patients reported to be diagnosed of CFTR-RD. Most patients were known to be compound heterozygotes with another pathogenic variant, primarily with p.Phe508del. In addition, two reported CBAVD patients were found to have elevated sweat chloride implying the diagnosis of CF/NC. Although a nonsense variant, severity of disease associated with this variant is widely reported as mild in literature which can be implicated to its location and resuting functional consequence. One clinical laboratory in ClinVar has classified it as pathogenic. Because CF/NC phenotype has been reported with this variant, and because CBAVD and ICP can also be categorized as manifestation of CF, this variant has been classified as pathogenic with respect to CF/NC phenotype. -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Dec 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change creates a premature translational stop signal (p.Gln1476*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the CFTR protein. This variant is present in population databases (rs374705585, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 11938439, 22020151, 25910067, 28544683). ClinVar contains an entry for this variant (Variation ID: 53947). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 27, 2020	This variant affects the last exon of CFTR and is predicted to escape nonsense mediated decay (NMD). The c.4426C>T alteration has been previously reported as a compound heterozygous change in multiple patients with variable clinical presentation ranging from cystic fibrosis to congenital absence of vas deference, and other CFTR-related disorders such as chronic pancreatitis (PMID: 21520337, 22020151, 23276700, https://cftr2.org/mutation/general/all_cf/Q1476X). In-vitro studies showed that this variant leads to the expression of a mature truncated form of CFTR that moderately affects the channel functioning and is responsive to treatment with lumacaftor, or a combination of both lumacaftor and tezacaftor (PMID: 30444886). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/282280) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.4426C>T (p.Gln1476Ter) variant on protein function. Based on the available evidence, the c.4426C>T (p.Gln1476Ter) variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient 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: PVS1_MOD, PS3_SUP, PM2_SUP, PM3_STR, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 09, 2024	The p.Q1476* variant (also known as c.4426C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4426. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CFTR, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. However, this variant has been reported in the literature in several individuals who are compound heterozygous for p.Q1476* and p.F508del: one individual with idiopathic pancreatitis was subsequently found to have elevated sweat chloride levels (Audrézet MP et al. Eur. J. Hum. Genet., 2002 Feb;10:100-6), two males had elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD), pancreatic sufficiency, and normal respiratory function (Bienvenu T et al. Clin. Genet., 2003 Sep;64:266-8), a third male was reported to have CBAVD only (Amato F et al. J Mol Diagn, 2012 Jan;14:81-9), another individual had moderate pulmonary symptoms with nasal polyposis and digital clubbing (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206), and the last individual had a history of bronchiectasis and pseudomonas infection (Sugunaraj JP et al. NPJ Genom Med, 2019 Sep;4:21). This variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 4, 2019). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	This nonsense variant causes the premature termination of CFTR protein synthesis. The frequency of this variant in the general population, 0.000039 (5/128820 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 28544683 (2017), 23276700 (2013), 12919146 (2003), 11938439 (2002)) and cystic fibrosis related disease (CFRD) (PMIDs: 25910067 (2015), 22020151 (2012), 21679131 (2011), 21520337 (2011), 17449517 (2007), 17003641 (2006), 12919146 (2003)). This variant is often detected in trans with another pathogenic CFTR variant in affected individuals (PMIDs: 28544683 (2017), 25910067 (2015), 22020151 (2012)). Functional studies have demonstrated this variant may mildly impact protein function, but additional studies are needed to determine the global impact of this variant on the CFTR gene or gene products (PMID: 30444886 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CFTR: PM3:Very Strong, PM2, PVS1:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2022	Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost within the PDZ interaction domain (Moyer et al., 1999), although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies demonstrate normal protein expression and modulator response, but reduced chloride channel function (Sharma et al., 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 31589614, 34426522, 30444886, 11938439, 12919146, 10562297, 17449517, 28603918, 21520337, 23276700, 25910067, 22020151, 25087612, 28544683, 21679131, 16784904, 17003641, 12578973, 11504857, 15758663) -

Hereditary pancreatitis

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2021	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2016

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

- -

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

Pathogenic:1

Likely 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

Mar 19, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.98

Vest4

0.69

GERP RS

5.5

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