chr7-117590397-T-A

Position:

chr7-117590397-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000492.4(CFTR):c.1724T>A(p.Phe575Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,603,458 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:7

Conservation

PhyloP100: 7.41

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 7-117590397-T-A is Pathogenic according to our data. Variant chr7-117590397-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 619674.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=3}. Variant chr7-117590397-T-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.1724T>A	p.Phe575Tyr	missense_variant	13/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1724T>A	p.Phe575Tyr	missense_variant	13/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250402

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135506

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:

0.0000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000186

AC:

AN:

1451366

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

721910

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000244

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 27, 2021	This sequence change replaces phenylalanine with tyrosine at codon 575 of the CFTR protein (p.Phe575Tyr). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and tyrosine. This variant is present in population databases (rs773569201, ExAC 0.002%). This missense change has been observed in individual(s) with recurrent pancreatitis (PMID: 17003641). ClinVar contains an entry for this variant (Variation ID: 619674). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2023	The p.F575Y variant (also known as c.1724T>A), located in coding exon 13 of the CFTR gene, results from a T to A substitution at nucleotide position 1724. The phenylalanine at codon 575 is replaced by tyrosine, an amino acid with highly similar properties. This variant was first reported in an infant with borderline sweat tests in conjunction with p.R117H; however, phase information was not provided (Sontag MK, et al. J. Pediatr. 2005 Sep; 147(3 Suppl):S83-8). In addition, this variant was identified in an individual with pancreatitis in trans with p.F508del (Keiles S, et al. Pancreas. 2006 Oct; 33(3):221-7). Experimental studies show that this alteration reduces CFTR function compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 16, 2019	CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2024	Variant summary: CFTR c.1724T>A (p.Phe575Tyr) results in a conservative amino acid change located in the ATP-binding domain (IPR009147) 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 250402 control chromosomes (gnomAD). c.1724T>A has been reported in the compound heterozygous state in at least 4 patients diagnosed with recurrent pancreatitis and unspecified CFTR-Related disease phenotypes, who carried the common pathogenic variant p.Phe508del in trans (Keiles_2006, McCague_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant has approximately 15-20% of wild-type activity as assessed in vitro (Raraigh_2018). The CFTR2 database reports that this variant has varying consequences and that some patients with this variant and another CF-causing variant have CF while others do not. The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 29805046, 30888834). ClinVar contains an entry for this variant (Variation ID: 619674). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 12, 2023	The CFTR c.1724T>A; p.Phe575Tyr variant (rs773569201) is reported in the literature in multiple individuals affected with pancreatitis and unspecified CFTR-related disorders who also carried pathogenic variant F508del and was confirmed in trans in at least one case (Keiles 2006, McCague 2019). This variant along with R117H has also been reported in an individual with borderline sweat chloride levels who was receiving treatment for CFTR-related disorders (Sontag 2005). This variant is reported in ClinVar (Variation ID: 619674) and is found in the non-Finnish European population with an allele frequency of 0.003% (3/113216 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein demonstrated activity of ~17% of wildtype (McCague 2019, Raraigh 2018). Computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on available information, this variant is considered to be likely pathogenic- mild. References: Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. McCague AF et al. Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis. Am J Respir Crit Care Med. 2019 May 1;199(9):1116-1126. PMID: 30888834. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. Sontag MK et al. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr. 2005 Sep;147(3 Suppl):S83-8. PMID: 16202790. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 10, 2020	- -

CFTR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 19, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2024

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.6

M;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

N;.;N;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.017

D;.;D;.

Sift4G

Uncertain

0.0090

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.79

MutPred

0.80

Gain of phosphorylation at F575 (P = 0.0561);.;.;.;

MVP

0.99

MPC

0.015

ClinPred

0.86

GERP RS

4.8

Varity_R

0.87

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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