chr7-117587731-G-A

Variant names:

• chr7-117587731-G-A
• rs193922503
• NM_000492.4:c.1585-8G>A

Variant summary

Our verdict is Pathogenic. The variant received 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, 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, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: -0.130
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 35828.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1585-8G>A		splice_region_variant, intron_variant	Intron 11 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1585-8G>A		splice_region_variant, intron_variant	Intron 11 of 26	1	NM_000492.4	ENSP00000003084.6

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

African (AFR) AF: 0.00 AC: 0 AN: 32196

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 85060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000378 AC: 4 AN: 1057030

Other (OTH) AF: 0.00 AC: 0 AN: 58402

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Jul 19, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: 23381846, 25066652). ClinVar contains an entry for this variant (Variation ID: 35828). This variant is also known as c.1717-8G>A. This variant has been observed in individuals with cystic fibrosis (PMID: 7512860, 23974870). This variant is not present in population databases (gnomAD no frequency). -

Feb 21, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 05, 2025

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 CFTR c.1585-8G>A (legacy name c.1717-8G>A) variant involves the alteration of a non-conserved intronic nucleotide. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 3' acceptor site. One predict the variant weakens the canonical 3' acceptor site. Four predict the variant creates a cryptic 3' acceptor site. These predictions are supported by experimental evidence such as minigene studies showing that the variant leads to the use of an alternative 3' splice site causing the addition of terminations codons to the RNA transcript and absent mature protein (Sosnay 2013, Raynal 2013, Sharma 2014). The variant was absent in 250742 control chromosomes. c.1585-8G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Savov 1994, Bisceglia 1994, Claustres 2000, Alonso 2006, Faucz 2007, Sosnay 2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7543317, 16126774, 17331079, 10923036, 7526928, 9099843, 9439669, 17718859, 19897426, 7512860, 23381846, 23974870, 25066652, 27067634). ClinVar contains an entry for this variant (Variation ID: 35828). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 31, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Moderate, PM2, PP1, PP3, PP4, PP5 -

CFTR-related disorder Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.63
PhyloP100		-0.13
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs193922503; hg19: chr7-117227785;