rs143486492

Positions:

chr7-117540120-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The ENST00000003084.11(CFTR):c.890G>A(p.Arg297Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000885 in 1,613,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:8

Conservation

PhyloP100: 6.39

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 177 pathogenic changes around while only 18 benign (91%) in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19872731).

BP6

Variant 7-117540120-G-A is Benign according to our data. Variant chr7-117540120-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54082.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=9, Likely_benign=7}. Variant chr7-117540120-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.890G>A	p.Arg297Gln	missense_variant	8/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.890G>A	p.Arg297Gln	missense_variant	8/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000567

AC:

142

AN:

250572

Hom.:

AF XY:

0.000554

AC XY:

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000907

AC:

1325

AN:

1460952

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

637

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152178

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000873

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2019	This alteration is classified as likely 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. -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient 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, PM3, PM5, BS3, BS4, BP2 -

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 26, 2022	The CFTR c.890G>A; p.Arg297Gln variant (rs143486492) is reported in the literature in multiple individuals affected with CFTR-related disorders (Casals 2004, Gallati 2009, Keiles 2006, Masson 2013, Sultan 2012). However, this variant has also been reported on the same chromosome as the 5T variant (Hughes 2001, Tzetis 2001), and did not segregate with disease in at least one family (Dorval 1995). This variant is reported in ClinVar (Variation ID: 54082), and is found in the non-Finnish European population with an allele frequency of 0.12% (153/128492 alleles) in the Genome Aggregation Database. The arginine at codon 297 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.717). Functional analyses of the variant protein show normal chloride channel activity (Chen 2000, Seibert 1997), but a defect in bicarbonate transport (Choi 2001). Due to conflicting information, the clinical significance of the p.Arg297Gln variant is uncertain at this time. References: Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004 28(4):374-9. PMID: 15097853. Chen EY et al. Cystic fibrosis transmembrane conductance regulator has an altered structure when its maturation is inhibited. Biochemistry. 2000 Apr 4;39(13):3797-803. PMID: 10736180. Choi JY et al. Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001 Mar 1;410(6824):94-7. PMID: 11242048. Dorval I et al. French CF family genotype analysis shows that the R297Q mutation is a rare polymorphism. Hum Mutat. 1995;6(4):334-5. PMID: 8680407. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. PMID: 20021716. Hughes D et al. Mutation and haplotype analysis of the CFTR gene in atypically mild cystic fibrosis patients from Northern Ireland. J Med Genet. 2001 Feb;38(2):136-9. PMID: 11288718. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. PMID: 17003641. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356. Seibert FS et al. Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. Biochemistry. 1997 Sep 30;36(39):11966-74. PMID: 9305991. Sultan M et al. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012 54(5):645-50. PMID: 22094894. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001 108(3):216-21. PMID: 11354633. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2023	The CFTR c.890G>A (p.Arg297Gln) variant has been reported in the published literature in individuals with mild/atypical CF, occurring in cis with the 5T allele (PMID: 11288718 (2001)). The variant has been reported in individuals with pancreatitis (PMID: 22094894 (2012), 28502372 (2017), 23951356 (2003), 17003641 (2006), 25033378 (2014)) and other CFTR-related disorders (PMID: 33946859 (2021)) as well as in healthy individuals who carried a CF-causing mutation on the opposing chromosome (PMID: 29589582 (2018), 8680407 (1995), 17489851 (2007)). Functional studies indicate this variant has a neutral effect on CFTR protein processing and chloride channel activity, but significantly reduced bicarbonate transport (PMID: 11242048 (2001), 9305991 (1997)). The frequency of this variant in the general population, 0.005 (24/4832 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2023	Published functional studies are inconclusive: reduced bicarbonate:chloride transport ratio with chloride channel function similar to wildtype (PMID: 9305991, 11242048); Observed in individuals with pancreatitis (PMID: 17003641, 22094894, 20846557); Observed in individuals with cystic fibrosis and/or an abnormal newborn screen (PMID: 11022925, 11288718, 11168024, 24418186); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 18456578, 11288708, 9305991, 11288718, 11242048, 20416310, 20021716, 24418186, 23514810, 20846557, 22094894, 17003641, 16778595, 8818956, 23951356, 11354633, 11022925, 29589582, 11168024, 23523379, 1284534, 7551394, 15097853, 11788091, 34782259, 32508047, 34996830, 8680407) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2021	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2024	Variant summary: CFTR c.890G>A (p.Arg297Gln) results in a conservative amino acid change located in the in the first transmembrane domain (IPR011527) and within the second cytoplasmic loop (Choi 2001) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 251720 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00056 vs 0.013), allowing no conclusion about variant significance. c c.890G>A has been reported in the literature in multiple individuals affected with a milder, atypical form of cystic fibrosis (Graham 1991,Hughes 2001) and was detected during newborn screening in neonates with positive sweat test results (Scotet 2000, Bozdogan_2021), however in Scotet_2000 the CFTR gene was not fully sequenced. The variant was also reported with various CFTR-related phenotypes, e.g. asthma (Tzetis 2001) infertility (Ravnik-Glavac 2001, Gallati 2009), and cholestasis (Wang_2020). However, multiple affected individuals were reported to carry another pathogenic CFTR variant (5T) in cis with the variant of interest (Graham 1991, Hughes 2001, Tzetis 2001), along with a family study indicating that the variant did not segregate with the disease (Dorval 1995). The variant was also reported in patients affected with chronic or recurrent pancreatitis (e.g. Casals 2004, Keiles 2006, Sutton 2010, Sultan 2012, Masson 2013, LaRusch_2014). However, some of these patients also carried the variant CFTR c.221G>A (p.Arg74Gln) (Keiles 2006, Masson 2013), and this co-occurring variant is internally classified as a VUS-possibly pathogenic variant for Chronic Pancreatitis Risk. Therefore, these data do not allow clear conclusions about variant significance. A functional study found the variant to be comparable to the wild type in maturation and chloride channel function (Seibert 1997), while another study reported a significantly reduced bicarbonate transport (Choi 2001). According to a later study, other variants that impair bicarbonate permeation may increase the risk for pancreatitis, but not for cystic fibrosis (LaRusch 2014). The following publications have been ascertained in the context of this evaluation (PMID: 24418186, 33572515, 15097853, 11242048, 8680407, 7551394, 20021716, 29589582, 11288718, 23514810, 17003641, 25033378, 23951356, 33946859, 20416310, 11788091, 31674704, 11168024, 11022925, 9305991, 11288708, 22094894, 16778595, 20846557, 8818956, 9691989, 11354633, 31450232, Graham_1991). ClinVar contains an entry for this variant (Variation ID: 54082). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 02, 2017	p.Arg297Gln variant in exon 8 of CFTR: This variant is not expected to have clin ical significance because it has been identified in 2 unaffected individuals in trans with a pathogenic variant (Dorval 1995). This variant has also been report ed in ClinVar (Variation ID 54082) and has been identified in 0.1% (155/126020) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs143486492). Computational prediction tools and con servation analysis suggest that the p.Arg297Gln variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS2, BP4. -

CFTR-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;D;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.1

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

N;.;.;N;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.025

D;.;.;D;.

Sift4G

Uncertain

0.038

D;.;.;D;.

Polyphen

0.13

B;.;.;.;.

Vest4

0.83

MVP

0.98

MPC

0.0044

ClinPred

0.037

GERP RS

5.4

Varity_R

0.72

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over