rs1800095

Variant names:

• chr7-117559655-G-A
• rs1800095
• NM_000492.4:c.1584G>A

Your query was ambiguous. Multiple possible variants found:

• 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.Glu528Glu) 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:40144): (CFTR antisense RNA 1)

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, Benign=6, Uncertain_significance=4, not_provided=3}. 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 rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1584G>A	p.Glu528Glu	splice_region_variant, synonymous_variant	Exon 11 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.221+1078C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1584G>A	p.Glu528Glu	splice_region_variant, synonymous_variant	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6

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

Jun 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

Aug 06, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 19, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3_MOD,PM3,PP3,BS2 -

not provided Uncertain:1 Benign:4

Sep 21, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: BP4, BS1, BS2 -

Dec 19, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS2, PS3_supporting, PM3 -

CFTR-related disorder Uncertain:1 Benign:3

May 20, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Jul 23, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2 Other:1

Dec 26, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 27, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

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. -

Oct 17, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis Benign:1 Other:1

Sep 01, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pancreatitis Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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;