rs747754623

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP2PP5

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). Synonymous variant affecting the same amino acid position (i.e. F1099F) has been classified as Likely benign.

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

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
congenital bilateral absence of vas deferens
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary chronic pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFTR links:

ENSG00000083622 (HGNC:40145):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000492.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

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 VariationId is 286681.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3297C>A	p.Phe1099Leu	missense_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS2	NR_199597.1 link	n.177+4491G>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3297C>A	p.Phe1099Leu	missense_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

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

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251098

AF XY:

0.00000737

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 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

African (AFR)

AF:

0.000299

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111756

Other (OTH)

AF:

0.0000331

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.000363

AC:

AN:

41354

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000685

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

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (PMID: 16189704, 26098992, 31788264, 33567498). ClinVar contains an entry for this variant (Variation ID: 286681). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 31788264, 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. -

Jul 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 21, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 08, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Pathogenic:2Uncertain:2

Apr 08, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3_strong, PS3 -

Jul 02, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CFTR-related disorder

Pathogenic:1

Jan 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

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

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Mar 23, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.;.

PhyloP100

2.3

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

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.64

gMVP

0.90

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over