rs747754623

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_000492.4(CFTR):c.3297C>A(p.Phe1099Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:4

Conservation

PhyloP100: 2.35

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:

(HGNC:):

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=11 (size 20) in uniprot entity CFTR_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117611738-C-A is Pathogenic according to our data. Variant chr7-117611738-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286681.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=4, Pathogenic=5}. Variant chr7-117611738-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3297C>A	p.Phe1099Leu	missense_variant	20/27	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.3297C>A	p.Phe1099Leu	missense_variant	20/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4491G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251098

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461450

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.000363

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000415

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2022	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1099 of the CFTR protein (p.Phe1099Leu). This variant is present in population databases (rs747754623, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis and/or cystic fibrosis (PMID: 16189704, 26098992, 33567498). ClinVar contains an entry for this variant (Variation ID: 286681). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 33567498). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2024	Variant summary: CFTR c.3297C>A (p.Phe1099Leu) results in a non-conservative amino acid change located in the second ABC transporter type 1 transmembrane domain (IPR011527) 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 1.6e-05 in 251098 control chromosomes (gnomAD). c.3297C>A has been reported in the literature in compound heterozygous state together with a pathogenic variant in individuals affected with Cystic Fibrosis or CFTR-related disorder, but was also reported in individuals presenting with intermediate sweat chloride levels either with features of CF or who were asymptomatic (e.g. McGinniss_2005, McCague_2019, Degrugillier_2019, Zhang_2021, Gunnet_2023). These data indicate that the variant is likely to be associated with disease, but commonly with a variable and/or milder phenotype. Several publications reported experimental evidence evaluating an impact on protein function and found that the variant is associated with reduced protein maturation efficiency and a decreased overall channel conductance, resulting in approximately 4-25% of WT channel function (e.g. Raraigh_2018, Degrugillier_2019, Zhang_2021, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 31788264, 26098992, 30888834, 16189704, 29805046, 26708955, 33567498, 38388235). ClinVar contains an entry for this variant (Variation ID: 286681). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 21, 2022	The p.F1099L variant (also known as c.3297C>A), located in coding exon 20 of the CFTR gene, results from a C to A substitution at nucleotide position 3297. The phenylalanine at codon 1099 is replaced by leucine, an amino acid with highly similar properties. The p.F1099L alteration has been reported as a variant of varying clinical consequences (VVCC) (The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed December 20, 2022). This variant has been confirmed in trans and identified likely in trans with a CFTR pathogenic variant in multiple individuals with clinical features of cystic fibrosis and CFTR-related disorders (McGinniss MJ et al. Hum Genet, 2005 Dec;118:331-8; Degrugillier F et al. Clin Case Rep, 2019 Nov;7:2128-2134; Zhang X et al. Life (Basel), 2021 Feb;11; Ambry internal data). This variant has 15% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed December 20, 2022). Another functional study showed that the maturation of p.F1099L was decreased compared to wild type CFTR (Degrugillier F et al. Clin Case Rep, 2019 Nov;7:2128-2134; Zhang X et al. Life (Basel), 2021 Feb;11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 08, 2017	- -

not provided

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2021	PM2, PM3_strong, PS3 -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The CFTR c.3297C>A variant is predicted to result in the amino acid substitution p.Phe1099Leu. This variant has been reported in the compound heterozygous state in an asymptomatic 2-month-old diagnosed with cystic fibrosis, in two pediatric patients diagnosed with cystic fibrosis, and in an individual with a negative sweat test who later presented with severe chronic rhinosinusitis (McGinniss et al. 2005. PubMed ID: 16189704; Degrugillier et al. 2019. PubMed ID: 31788264; Zhang et al. 2021 PubMed ID: 33567498). In vitro studies show that this variant results in reduced protein processing and maturation, fewer CFTR channels at the cell surface and, reduced overall CFTR protein function (Raraigh et al. 2018. PubMed ID: 29805046; Degrugillier et al. 2019. PubMed ID: 31788264; Zhang et al. 2021 PubMed ID: 33567498). This variant is listed as a variant of varying clinical consequence (VVCC) in the CFTR2 database. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.059

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.50

D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

1.0

N;.;.;N;.

REVEL

Uncertain

0.62

Sift

Benign

0.64

T;.;.;T;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MutPred

0.91

Loss of MoRF binding (P = 0.1263);.;.;.;.;

MVP

1.0

MPC

0.0086

ClinPred

0.19

GERP RS

3.0

Varity_R

0.64

gMVP

0.90

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