rs186045772

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3PP5_Strong

The NM_000492.4(CFTR):c.3222T>A(p.Phe1074Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,636 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 drug response (★★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:9U:2O:1

Conservation

PhyloP100: 1.76

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a helix (size 50) in uniprot entity CFTR_HUMAN there are 11 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, 0.833

PP5

Variant 7-117611663-T-A is Pathogenic according to our data. Variant chr7-117611663-T-A is described in ClinVar as [drug_response]. Clinvar id is 53688.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, drug_response=1, Uncertain_significance=2, Pathogenic=2}. Variant chr7-117611663-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3222T>A	p.Phe1074Leu	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.3222T>A	p.Phe1074Leu	missense_variant	20/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+4566A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251044

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: drug response

Submissions summary: Pathogenic:9Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2024	Variant summary: CFTR c.3222T>A (p.Phe1074Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 253492 control chromosomes. The variant has been reported in cis with 5T allele in individuals affected with Non-classic Cystic Fibrosis (Casals_1997, Casals_2000). In those three patients, authors did not find a pathogenic variant in the second allele, however in additional patients with CBVAD or CF, pathogenic variants were detected on second allele (Casals_2000, Terlizzi_2019). Furthermore, other individuals have been reported with a second pathogenic allele who have intermmediate sweat chloride levels, resulting in an inconclusive CF diagnosis (e.g. Colombo_2006, Padoan_2006, Gonska_2021). These data indicate that the variant may be associated with disease. At least one publication reports that this variant leads to impaired chloride transport and processing (Van Goor_2013, Prins_2020), consistent with the mild CF disease associated with this variant. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 10875853, 9439669, 24813944, 15126740, 8702904, 23017188, 17003641, 26574590, 25033378, 28736296, 30888834, 20416310, 16801189, 32934006, 30561903, 32150665, 23687349, 23891399, 34814176). ClinVar contains an entry for this variant (Variation ID: 53688). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 17, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 11, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2023	The p.F1074L variant (also known as c.3222T>A), located in coding exon 20 of the CFTR gene, results from a T to A substitution at nucleotide position 3222. The phenylalanine at codon 1074 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in four individuals in the Italian cystic fibrosis registry; however, full genotype and phenotype information was not provided (Salvatore D et al. Pediatr. Pulmonol., 2019 Feb;54:150-157). An in vitro study suggested that this alteration results in deficient CFTR protein maturation and chloride transport (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). In some cases, this alteration has been reported to occur in cis with the 5T variant (Casals T et al. Hum. Genet., 1997 Dec;101:365-70; Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83). The p.F1074L variant has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 11, 2019). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 13, 2021	This sequence change replaces phenylalanine with leucine at codon 1074 of the CFTR protein (p.Phe1074Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs186045772, ExAC 0.002%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens (PMID: 9439669, 10875853, 16801189, 17003641, 17407489). ClinVar contains an entry for this variant (Variation ID: 53688). 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: 23891399). 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

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2017	The F1074L pathogenic variant in the CFTR gene has been reported previously in cis with the 5T allele in siblings with a mild cystic fibrosis phenotype, but no other variant was found on the opposite CFTR allele (Casals et al., 1997). The F1074L variant has also been reported in cis with the 5T allele and phase unknown with the G551D variant in an individual with congenital bilateral absence of the vas deferens (Casals et al., 2000). Functional studies demonstrate that F1074L is associated with reduced chloride transport (Van Goor et al., 2014). The F1074L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1074L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. The F1074L variant is reported in the CFTR2 database as being associated with varying consequences. Missense variants in nearby residues (G1069R, R1070Q, R1070W, L1077P) have been reported in the Human Gene Mutation Database in association with cystic fibrosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret F1074L as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2023	The CFTR c.3222T>A; p.Phe1074Leu variant (rs186045772) is reported in the literature in individuals affected with CFTR-related disorders (CFTR-RD), such as pancreatitis, congenital bilateral absence of the vas deferens, or other mild symptoms (Casals 1997, Casals 2000, Colombo 2007, Coste 2004, Keiles 2006, Ooi 2010, Padoan 2006, see links to CFTR databases). Some of these individuals carried a CF-causing variant on the opposite chromosome, and several individuals were reported to carry the mild 5T variant on the same chromosome. While this indicates that the p.Phe1074Leu variant can be part of a complex variant with 5T ([c.3222T>A;5T]), insufficient information was provided by some of the cited authors to determine whether this is always the case. The p.Phe1074Leu variant is reported in ClinVar (Variation ID: 53688), and it is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.804). Functional analyses of the variant protein show reduced expression and decreased chloride transport (Van Goor 2014). While available evidence suggests that the complex variant [c.3222T>A;5T] is likely pathogenic, the clinical significance of c.3222T>A; p.Phe1074Leu alone is uncertain at this time. References: Link to CFTR2 database: https://cftr2.org/mutation/scientific/pi/F1074L Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=457 Casals T et al. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes. Hum Genet. 1997 Dec;101(3):365-70. PMID: 9439669. Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000 Jul;15(7):1476-83. PMID: 10875853. Colombo C et al. Is early identification of asymptomatic infants with 'mild' CFTR genotypes clinically useful? Acta Paediatr. 2007 Mar;96(3):477-9. PMID: 17407489. Coste A et al. Atypical sinusitis in adults must lead to looking for cystic fibrosis and primary ciliary dyskinesia. Laryngoscope. 2004 May;114(5):839-43. PMID: 15126740. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Ooi CY et al. Genetic testing in pancreatitis. Gastroenterology. 2010 Jun;138(7):2202-6, 2206.e1. PMID: 20416310. Padoan R et al. Identification of the 5T-12TG allele of the cystic fibrosis transmembrane conductance regulator gene in hypertrypsinaemic newborns. Acta Paediatr. 2006 Jul;95(7):871-3. PMID: 16801189. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. PMID: 23891399. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 17, 2020

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 08, 2024

- -

ivacaftor response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;D;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.0

D;.;.;D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.96

MutPred

0.90

Loss of helix (P = 0.1299);.;.;.;.;

MVP

1.0

MPC

0.0074

ClinPred

0.99

GERP RS

4.5

Varity_R

0.91

gMVP

0.98

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