Variant rs895394181 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117648320-A-G is Pathogenic according to our data. Variant chr7-117648320-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 500071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3874-4522A>G		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3874-4522A>G		intron_variant		1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.0000735

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000723

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Feb 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change falls in intron 23 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cystic fibrosis (PMID: 21909392, 30389601). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 4005+5727A>G. ClinVar contains an entry for this variant (Variation ID: 500071). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30389601). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: CFTR c.3874-4522A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3' acceptor site and one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence from sequencing RNA from compound heterozygous individuals with the variant, as well as a minigene assay, that shows this variant indeed affects mRNA splicing (Bergougnoux_2019). This study showed that the variant results in aberrant splicing which leads to the inclusion of a 125bp pseudo-exon, predicted to result in a premature stop codon, in 76% of RNA transcripts. The variant was absent in 31150 control chromosomes (gnomAD). c.3874-4522A>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with Cystic Fibrosis and CFTR-related disorders, including cases where it has been confirmed to be in trans with a pathogenic variant (e.g. Roth_2011, Bergougnoux_2019 Morris-Rosendahl_2020). These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=4)/likely pathogenic (n=1) or VUS (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 23, 2022	CFTR c.3874-4522A>G has been identified in multiple individuals with features of cystic fibrosis including one who has a known CF-causing variant on the opposite chromosome. This CFTR variant has been reported in ClinVar (Variation ID: 500071), but is absent from a large population dataset. Functional studies demonstrate that this deep intronic variant creates a cryptic splice site that leads to aberrant splicing. We consider CFTR c.3874-4522A>G to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2022	The c.3874-4522A>G intronic variant (also known as c.4005+5727A>G) results from an A to G substitution 4522 nucleotides before coding exon 24 in the CFTR gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in trans with a pathogenic CFTR mutation in an individual with classic cystic fibrosis (CF), and it has been observed in individuals with CFTR-related disorders, some of whom have other CFTR variants of undetermined phase (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475; Roth EK et al. PLoS One, 2011 Aug;6:e24445). One experimental study shows that this variant disrupts mRNA splicing; however, the variant's effect on splicing is incomplete (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475) This nucleotide position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:4Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2023	Observed multiple times with a second CFTR causing variant in patients with cystic fibrosis or CFTR-related disorders, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Roth et al., 2011, Claustres et al., 2017); No data available from control populations to assess the frequency of this variant; Also known as 4005 + 5727A>G; This variant is associated with the following publications: (PMID: 25569440, 30389601, 31845523, 32017858, 35850704, 36349818, 21909392, 35858753) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2022	The frequency of this variant in the general population, 0.000024 (1/41384 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported to co-occur with other pathogenic CFTR variants and has been associated with various phenotypes including male infertility and cystic fibrosis with pancreatic insufficiency (PMID: 30389601 (2019), 21909392 (2011), CFTR-France https://cftr.iurc.montp.inserm.fr/). In addition, a splicing analysis performed using cells taken from multiple individuals with cystic fibrosis has found that this variant results in aberrant splicing (PMID: 30389601 (2019)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	The CFTR c.3874-4522A>G variant (rs895394181) is reported in the literature in multiple individuals affected with cystic fibrosis and CFTR related disorders (Bergougnoux 2019, Roth 2011, Shen 2022, Su 2023). This variant is also reported in ClinVar (Variation ID: 500071) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. A minigene assay found this variant affects mRNA splicing resulting in the inclusion of a 125bp pseudo-exon that is predicted to result in a premature stop codon in a majority of RNA transcripts (Bergougnoux 2019). Based on available information, this variant is considered to be likely pathogenic. References: Bergougnoux A et al. Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene. J Cyst Fibros. 2019 Jul;18(4):468-475. PMID: 30389601. Roth EK et al. The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. PLoS One. 2011;6(8):e24445. PMID: 21909392. Shen Y et al. Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China. J Med Genet. 2022 Jul 20;60(3):310–5. PMID: 35858753. Su Y et al. Case report of a pediatric Chinese cystic fibrosis patient with the c.1521_1523delCTT/c.3874-4522A>G genotype. Pediatr Pulmonol. 2023 Feb;58(2):556-558. PMID: 36349818. -

Cystic fibrosis;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

CFTR-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2023

The CFTR c.3874-4522A>G variant is predicted to interfere with splicing. This variant, previously reported as c.4005+5727A>G, has been reported in patients with cystic fibrosis (Bonini et al. 2015. PubMed ID: 25569440; Roth et al. 2011. PubMed ID: 21909392; Ellingford et al. 2022. PubMed ID: 35850704). This variant was also described in ten additional individuals with various CFTR-related phenotypes ranging from male infertility to cystic fibrosis with pancreatic insufficiency (Bergougnoux et al. 2018. PubMed ID: 30389601) and was reported in another study in the compound heterozygous state in twelve patients with cystic fibrosis (Morris-Rosendahl et al. 2020. PubMed ID: 32017858). In vitro splicing analysis indicates that this change results in inclusion of 125 bp (Bergougnoux et al. 2018. PubMed ID: 30389601). In Clinvar, this variant has been listed from 'uncertain' to 'pathogenic' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/500071/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, we classify this variant as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.6

DANN

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

rs895394181

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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