rs1800095

Positions:

• chr7-117559655-G-A
• chr7-117559655-G-C
• chr7-117559655-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_000492.4(CFTR):​c.1584G>A​(p.Glu528=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0201 in 1,609,992 control chromosomes in the GnomAD database, including 394 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.020 (357 hom.)
• Consequence: CFTR NM_000492.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9939
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:15 O:3
• Conservation: PhyloP100: 6.38

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 7-117559655-G-A is Benign according to our data. Variant chr7-117559655-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43576.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=4, not_provided=3, Benign=7}. Variant chr7-117559655-G-A is described in Lovd as [Likely_benign]. Variant chr7-117559655-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.017 (2580/152136) while in subpopulation AMR AF= 0.0302 (462/15286). AF 95% confidence interval is 0.0279. There are 37 homozygotes in gnomad4. There are 1239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1584G>A	p.Glu528=	splice_region_variant, synonymous_variant	11/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.221+1078C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1584G>A	p.Glu528=	splice_region_variant, synonymous_variant	11/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2581 AN: 152020 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.0167 AC: 4190 AN: 250582 Hom.: 48 AF XY: 0.0166 AC XY: 2252 AN XY: 135544

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00288

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0204 AC: 29752 AN: 1457856 Hom.: 357 Cov.: 29 AF XY: 0.0200 AC XY: 14522 AN XY: 725568

Gnomad4 AFR exome AF: 0.00315

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00316

Gnomad4 FIN exome AF: 0.0239

Gnomad4 NFE exome AF: 0.0236

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0170 AC: 2580 AN: 152136 Hom.: 37 Cov.: 32 AF XY: 0.0167 AC XY: 1239 AN XY: 74370

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0234

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0192 Hom.: 54

Bravo AF: 0.0165

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.0220

EpiControl AF: 0.0213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:15 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, BS1, BS2, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2020	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CFTR: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 18, 2022	BS2, PS3_supporting, PM3 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

CFTR-related disorder Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 01, 2019	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:2 Other:1

not provided, no classification provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2013	Glu528Glu in exon 11 of CFTR (c.1584G>A, historically known as c.1716G>A): This variant has been shown to result in exon skipping in about 10% of transcripts; however, it is prevalent in many populations (highest allele frequency 6.3% in Puerto Ricans; 1000 Genomes Project; rs1800095) and therefore not expected to cause highly penetrant, Mendelian disease. Consistent with this, it has been identified in combination with a severe CF-causing variant in control populations (Rosendahl 2013). However, several studies have suggested that it may be a predisposing factor to idiopathic chronic pancreatitis, although it is unclear if this predisposition is statistically significant (Casals 2004; Rosendahl 2013; Maire 2003). In summary, this variant may be a risk factor for CF-related disease (chronic pancreatitis). It is not expected to lead to disease on its own or in combination with a pathogenic CFTR variant, but may act in conjunction with other genetic and/or environmental risk factors. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -

Hereditary pancreatitis Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 01, 2020	- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Pancreatitis Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Uncertain significance and reported on 02/20/2018 by GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1800095; hg19: chr7-117199709; COSMIC: COSV50089416; COSMIC: COSV50089416;