rs397508809

Positions:

• chr7-117538986-AGAAT-A

Variant summary

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

The NM_000492.4(CFTR):​c.870-1113_870-1110delGAAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 1.26

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 7-117538986-AGAAT-A is Pathogenic according to our data. Variant chr7-117538986-AGAAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.870-1113_870-1110delGAAT		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.870-1113_870-1110delGAAT		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 12, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 19759008). ClinVar contains an entry for this variant (Variation ID: 54075). This variant has been observed in individuals with cystic fibrosis (PMID: 19759008, 21783433). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 07, 2017	The c.870-1110_870-1113delGAAT intronic variant, located in intron 7 of the CFTR gene, results from a deletion of 4 nucleotides within intron 7 of the CFTR gene. Two studies evaluating mRNA from patients' nasal epithelial cells revealed the inclusion of 97 base pairs of intron 7 sequence between exons 7 and 8 (Faà V et al. J. Biol. Chem., 2009 Oct;284:30024-31; Costa C et al. J. Cyst. Fibros., 2011 Dec;10:479-82). A minigene assay of wild-type and mutant constructs further demonstrated that this deletion abolished the binding site for hnRNPA2/B1 and created a binding site for SRp75 splicing factor (Faà V et al. J. Biol. Chem., 2009 Oct;284:30024-31). Multiple patients, mostly of Italian or French origin, have been described to be heterozygous for this alteration and a second pathogenic mutation; methods for phasing (cis vs. trans) were not described. Reported phenotypes and age at diagnosis have varied, but are most consistent with classic cystic fibrosis (Faà V et al. J. Biol. Chem., 2009 Oct;284:30024-31; Costa C et al. J. Cyst. Fibros., 2011 Dec;10:479-82). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 21, 2023

- -

Cystic fibrosis;C5924204: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 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -48

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508809; hg19: chr7-117179040;