chr7-117667029-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000492.4(CFTR):c.4364C>G(p.Ser1455*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000105 in 1,613,946 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. There are 5 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117667029-C-G is Pathogenic according to our data. Variant chr7-117667029-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117667029-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.4364C>G	p.Ser1455*	stop_gained	Exon 27 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.4364C>G	p.Ser1455*	stop_gained	Exon 27 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

251040

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135646

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727194

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Uncertain:1

Jun 09, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: The c.4364C>G (p.Ser1455*) variant in CFTR gene is a nonsense change predicted cause loss of last 26 amino acids of the protein. This variant is found in 1/121108 control chromosomes at a frequency of 0.000008, which does not exceed the maximal expected frequency of a pathogenic allele (0.0129) in this gene. Although in vitro testing showed stable mutant protein and normal chloride channel function in epithelial expression (Mickle_1998), the CFTR protein missing the last 26 amino acids in vivo is expected to associate with elelvated chloride level in patients carrying this variant due to mistargeting of the mutant to the basolateral membrane (Moyer_1999). The variant has been reported in multiple affected individuals and was shown to segregate with the disease in CF families. The variant, by its nature and based on clinical and functional data, is expected to cause non-classic CF. Two reputable databases have classified this variant as pathogenic. Taken together, the variant is classified as Pathogenic. -

Aug 20, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 06, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1455* pathogenic mutation (also known as c.4364C>G), located in coding exon 27 of the CFTR gene, results from a C to G substitution at nucleotide position 4364. This changes the amino acid from a serine to a stop codon within coding exon 27. This alteration occurs at the 3' terminus of theCFTR gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 26 amino acids of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region is critical for protein function (Ambry internal data). This alteration 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 July 6, 2023). In one study, this alteration was detected in trans with a gross deletion in mother and daughter who had isolated elevated sweat chloride levels, but no clinical manifestation of cystic fibrosis (Mickle JE et al. Hum. Mol. Genet., 1998 Apr;7:729-35). The variant was also detected with p.F508del in monozygotic twin brothers who exhibited more severe lung symptoms with Pseudomonas colonization of the upper airway (Kalampouka E et al. Arch. Bronconeumol., 2014 Nov;50:499-500). In another study, two siblings with p.F508del in trans with this alteration had elevated sweat chloride levels and no respiratory symptoms or pancreatic involvement (Salvatore D et al. Am. J. Med. Genet. A, 2005 Mar;133A:207-8). Functional studies indicated that this mutation may not alter biosynthesis or maturation of the CFTR protein but may inhibit channel activity and chloride transport (Mickle JE et al. Hum. Mol. Genet., 1998 Apr;7:729-35; Ostedgaard LS et al. Proc. Natl. Acad. Sci. U.S.A., 2003 Feb;100:1937-42; Benharouga M et al. J. Biol. Chem., 2003 Jun;278:22079-89; Sharma N et al. PLoS Genet, 2018 Nov;14:e1007723). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser1455*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the CFTR protein. This variant is present in population databases (rs121909043, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 17662673, 23276700, 24388274, 25304080, 27728908). This variant is also known as delta26. ClinVar contains an entry for this variant (Variation ID: 7223). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 9499426, 10562297, 12651858). For these reasons, this variant has been classified as Pathogenic. -

CFTR-related disorder

Pathogenic:2

Sep 15, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 20, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:1

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Oct 23, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sweat chloride elevation without cystic fibrosis

Pathogenic:1

Mar 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

Vest4

0.78

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