rs193922503

Positions:

• chr7-117587731-G-A
• chr7-117587731-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1585-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,401,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: -0.130

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117587731-G-A is Pathogenic according to our data. Variant chr7-117587731-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35828.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587731-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1585-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1585-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1401288 Hom.: 0 Cov.: 24 AF XY: 0.00000285 AC XY: 2 AN XY: 700768

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2023	The c.1585-8G>A intronic pathogenic mutation (also known as c.1717-8G>A) results from a G to A substitution 8 nucleotides upstream from coding exon 12 in the CFTR gene. This mutation was first identified in the heterozygous state in two cousins with recurrent pulmonary infections, pancreatic insufficiency, and positive sweat chloride tests (Savov A et al. Hum. Molec. Genet. 1994;3(1):57-60); one cousin also carried the p.F508del mutation on the opposite allele. This alteration has also been reported as a rare mutation identified in Spanish cystic fibrosis patients (Alonso MJ et al. Ann Hum Genet 2007;71(Pt2):194-201). Functional in vitro studies found that cells carrying this pathogenic mutation did not produce correctly spliced RNA or mature CFTR protein (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). The c.1585-8G>A mutation produces an RNA transcript that includes the six last nucleotides of intron 11 (TAATAG) at the 5' end of exon 12, leading to the in-frame inclusion of two consecutive premature termination codons (Raynal C et al. Hum Mutat 2013;34(5):774-84). This mutation is typically associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). In addition, this variant has been detected in the homozygous state by our laboratory. Based on the supporting evidence, c.1585-8G>A is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 21, 2018	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 28, 2023	This sequence change falls in intron 11 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 individuals with cystic fibrosis (PMID: 7512860, 23974870). This variant is also known as c.1717-8G>A. ClinVar contains an entry for this variant (Variation ID: 35828). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23381846, 25066652). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2020	PS3, PS4_Moderate, PM2, PP1, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 31, 2016	- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: 2
DS_AL_spliceai		0.92		Position offset: 8

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922503; hg19: chr7-117227785;