7-117589476-G-T

Position:

• chr7-117589476-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1680-877G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: -1.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117589476-G-T is Pathogenic according to our data. Variant chr7-117589476-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 53331.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117589476-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1680-877G>T		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1680-877G>T		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2022	The c.1680-877G>T intronic pathogenic mutation (also known as c.1679+1643G>T and 1811+1643G>T) results from a G to T substitution 877 nucleotides upstream from coding exon 13 in the CFTR gene. In our clinical cohort, this alteration has been detected in the homozygous state in a few apparently unrelated individuals reported to have clinical presentations of cystic fibrosis (CF). This alteration was also identified in trans with p.F508del in an individual with CF; RNA studies of this individual's primary nasal epithelia cells revealed that this alteration resulted in an aberrant transcript with 53 extra nucleotides. The aberrant transcript was in lower abundance than the p.F508del transcript, suggestive of non-sense mediated decay. Consistent with this observation, a minigene bearing this alteration showed a complete loss of CFTR protein in HEK293 cells (Lee M et al. Am. J. Hum. Genet., 2017 May;100:751-765). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2023	Variant summary: CFTR c.1680-877G>T (also known as c.1679+1643G>T and 1811+1643G>T in publication and database) is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a 5 donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and this variant results in creating a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15) (Lee_2017). The variant was absent in 31352 control chromosomes (gnomAD). c.1680-877G>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Cystic Fibrosis (Schrijver_2016, Lee_2017, Raraigh_2022). These data indicate that the variant may be associated with disease. Six ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=4) and likely pathogenic (n=2), including CFTR2 classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 18, 2024	This sequence change falls in intron 12 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. This variant is present in population databases (rs397508261, gnomAD 0.1%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 26708955, 28475858, 29970830). This variant is also known as c.1679+1643G>T. ClinVar contains an entry for this variant (Variation ID: 53331). Studies have shown that this variant alters CFTR gene expression (PMID: 28475858). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 16, 2023	Criteria applied: PS3,PM3_STR,PM2_SUP,PP3; Identified as compund heterozygous with NM_000492.4:c.1521_1523del -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 27, 2024	The CFTR c.1680-877G>T variant (also known as 1811+1643G>T) has been reported in the published literature in several individuals affected with cystic fibrosis (CF) (PMIDs: 34782259 (2021), 30296588 (2018), 29970830 (2018), 28475858 (2017), 26574590 (2015), 22608296 (2012)). Experimental studies have shown that this variant activates a cryptic donor site that causes the inclusion of a 53 bp pseudo exon between exons 12 and 13 in the final CFTR mRNA and a frameshift in the coding sequence (p.Ala561Serfs*15). This results in complete loss of normal CFTR protein (PMID: 28475858 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 27, 2021	PP5, PM2, PS3 -

CFTR-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 23, 2022

The CFTR c.1680-877G>T variant is predicted to interfere with splicing. This variant is predicted to possibly introduce a novel splice site (Alamut Visual Plus v1.6.1). This variant has been reported in individuals with autosomal recessive cystic fibrosis (Schrijver et al. 2016. PubMed ID: 26708955; https://cftr2.org/). This variant is also known as 1811+1643G>T and c.1679+1643G>T. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In summary, we classify this variant as likely pathogenic. -

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_noAF	Benign	-0.90
CADD	Benign	19
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397508261; hg19: chr7-117229530;