rs397508788

Positions:

chr7-117535383-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000492.4(CFTR):c.715G>A(p.Gly239Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10O:1

Conservation

PhyloP100: 2.13

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 5 ACMG points.

PM1

In a transmembrane_region Helical; Name=4 (size 20) in uniprot entity CFTR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.715G>A	p.Gly239Arg	missense_variant	6/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.715G>A	p.Gly239Arg	missense_variant	6/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251404

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000877

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 16, 2024	The p.G239R variant (also known as c.715G>A), located in coding exon 6 of the CFTR gene, results from a G to A substitution at nucleotide position 715. The glycine at codon 239 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in an 80-year-old individual with chronic bronchorrhea and sinusitis; a second CFTR variant was not identified (Bienvenu T et al. Hum. Hered.;45:53-4). This variant was also reported in an adult with cystic fibrosis without a second CFTR variant identified (Gilljam M et al. Chest, 2004 Oct;126:1215-24). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 03, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 239 of the CFTR protein (p.Gly239Arg). This variant is present in population databases (rs397508788, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis or bronchiestasis (PMID: 7534748, 10445602, 15486385, 29944384). ClinVar contains an entry for this variant (Variation ID: 54046). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2018	The CFTR c.715G>A; p.Gly239Arg variant (rs397508788) has been reported in individuals affected with mild cystic fibrosis and pancreatic sufficiency (Bienvenu 1995, Gilljam 2004, SickKids CFTR database) and one individual with symptomatic diffuse bronchiectasis (Puechal 1999). This variant is reported in ClinVar (Variation ID: 54046), and is found in the general population with an overall allele frequency of 0.007% (21/282,796 alleles) in the Genome Aggregation Database. The glycine at codon 239 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Gly239Arg variant is uncertain at this time. References: SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=146 Bienvenu T et al. Identification of a novel missense mutation G239R in exon 6a of the CFTR gene. Hum Hered. 1995; 45(1):53-4. Gilljam M et al. Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood. Chest. 2004 Oct;126(4):1215-24. Puechal X et al. Increased frequency of cystic fibrosis deltaF508 mutation in bronchiectasis associated with rheumatoid arthritis. Eur Respir J. 1999 Jun;13(6):1281-7. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2024	Variant summary: CFTR c.715G>A (p.Gly239Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251404 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in CFTR causing Cystic Fibrosis (7.6e-05 vs 0.013), allowing no conclusion about variant significance c.715G>A has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Gilljam_2004, Desai_2018), bronchiectasis (e.g., Puechal_1999), and chronic bronchorrhea and sinusitis with a sweat chloride level of 60 mmol/l (Bienvenu_1995), however no second variant was reported in these individuals. These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 58% of normal chloride channel conductance relative to wild type (e.g., Bihler_2023 (bioRxiv preprint, no PMID)). The following publications have been ascertained in the context of this evaluation (PMID: 7534748, 29944384, 15486385, 10445602, 34996830). ClinVar contains an entry for this variant (Variation ID: 54046). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.48

T;.;.;T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

T;T;T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.34

N;.;.;.;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.15

N;.;.;N;.

REVEL

Uncertain

0.49

Sift

Benign

0.33

T;.;.;T;.

Sift4G

Benign

0.19

T;.;.;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.85

MutPred

0.91

Gain of methylation at G239 (P = 0.0014);Gain of methylation at G239 (P = 0.0014);Gain of methylation at G239 (P = 0.0014);.;Gain of methylation at G239 (P = 0.0014);

MVP

0.91

MPC

0.0039

ClinPred

0.052

GERP RS

2.1

Varity_R

0.24

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: 28

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