7-117667022-C-T

Position:

chr7-117667022-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000492.4(CFTR):c.4357C>T(p.Arg1453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,034 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1453Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 6 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:2

Conservation

PhyloP100: 1.61

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_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022263259).

BP6

Variant 7-117667022-C-T is Benign according to our data. Variant chr7-117667022-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=11}.

BS2

High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4357C>T	p.Arg1453Trp	missense_variant	27/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.4357C>T	p.Arg1453Trp	missense_variant	27/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152156

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:

0.00580

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251036

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000390

AC:

570

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000396

AC XY:

288

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0132

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000236

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00581

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000161

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	Observed in individuals with pancreatitis or bronchiectasis as well as in healthy controls (Lee et al., 2003; Fujiki et al., 2004; Keiles et al., 2006; Aoyagi et al., 2009; Kondo et al., 2015; Nakano et al., 2015; Iso et al., 2019; Fujita et al., 2022; Ni et al., 2022); Published functional studies demonstrate reduced channel opening probability, normal gene expression and splicing, and no significant effect on cAMP-activated anion exchange (Lee et al., 2003; Iso et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.4489C>T; This variant is associated with the following publications: (PMID: 20981092, 34996830, 35387941, 12952861, Jefri[thesis]2018, 20571109, Yoshimura[abstract]2012, 26089335, 25492507, 30992994, 22664493, 20879059, 19383231, 11504857, 17003641, 15121783, 12166651, 35313924, 22515107) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2020	The CFTR c.4357C>T; p.Arg1453Trp variant (rs4148725) is reported in the literature in individuals with chronic pancreatitis and bronchiectasis, as well as in control individuals (Keiles 2006, Kondo 2015, Lee 2003, Nakano 2015). While one study reported significant enrichment of this variant in individuals with idiopathic pancreatitis (Kondo 2015), this study included a small number of subjects, and a second study did not observe significant enrichment among pancreatitis patients (Nakano 2015). The p.Arg1453Trp variant is reported in ClinVar (Variation ID: 411121) and is found in the East Asian population with an allele frequency of 0.1% (20/19892 alleles) in the Genome Aggregation Database. The arginine at codon 1453 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, chloride channel activity assays suggest that the p.Arg1453Trp variant exhibits a substantially reduced probability of opening, though this results in only a mild reduction in channel current (Lee 2003). Due to limited information, the clinical significance of the p.Arg1453Trp variant is uncertain at this time. References: Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. Lee JH et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 Sep 15;12(18):2321-32. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. -

Cystic fibrosis

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 22, 2024	The p.R1453W variant (also known as c.4357C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4357. The arginine at codon 1453 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was observed in a Korean patient with bronchiectasis, but also in two healthy control individuals. The authors demonstrated that although this variant had no effect on the expression of the protein, there was a reduction in chloride channel function (Lee JH, et al. Hum Mol Genet. 2003;12(18):2321-2332). This variant has been observed in multiple Japanese cohorts of individuals diagnosed with pancreatitis (Fujiki K et al. J Med Genet. 2004;41(5):e55; Kondo S et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2015 Aug;309:G260-9; Iso M et al. Hum Genome Var, 2019 Apr;6:17; Fujita S et al. Endocr J, 2022 Sep;69:1101-1108). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

CFTR-related disorder

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 08, 2024	The CFTR c.4357C>T variant is predicted to result in the amino acid substitution p.Arg1453Trp. This variant has been reported in patients with idiopathic pancreatitis or bronchitis from Japan and Korea as well as in healthy individuals (Kondo et al. 2015. PubMed ID: 26089335; Kim et al. 2010. PubMed ID: 20879059; Lee et al. 2003. PubMed ID: 12952861). However, this variant does not appear to affect CFTR protein expression and results are conflicting on whether chloride channel activity is affected (Lee et al. 2003. PubMed ID: 12952861). This variant is reported in 0.10% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 25, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 22, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 14, 2020

Variant summary: CFTR c.4357C>T (p.Arg1453Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 258140 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the maximum expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.0011 vs 0.013), allowing no conclusion about variant significance. However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0232 (in the jMorp database). This frequency is about 1.7-fold higher than the maximum expected for a pathogenic variant, suggesting the variant could be a benign polymorphism. Though the variant, c.4357C>T, has not been reported in the literature in individuals affected with Cystic Fibrosis (CF) or Congenital Bilateral Absence of the Vas Deferens (CBAVD), it was found in several Japanese patients with pancreatitis, and was also described in some patients affected with diffuse panbronchiolitis, bronchiectasis and asthma. These reports do not provide unequivocal conclusions about association of the variant with the reported disease phenotypes. In two Japanese case-control studies, this variant was not significantly overrepresented in pancreatitis patient cohorts compared to controls (Fujiki_2004, Nakano_2015). In two other studies however, the frequency of this variant was higher in pancreatitis patients than in controls, though the sample sizes were small (Kondo_2015, Iso_2019). Therefore, whether this variant is a risk variant to pancreatitis needs to be further investigated. In one ICP patient, this variant co-occurred with another pathogenic variant (c.194+2T>C) and a risk variant (c.101A>G/p.Asn34Ser) in the SPINK1 gene (Nakano_2015), suggesting this variant was not a primary cause of disease in the patient. One functional study has shown that this variant leads to 37% decrease in whole cell chloride currents due to significantly reduced (by 78%) channel opening probability (Lee_2003), but the clinical significance of this effect on the associated pathophysiology of disease is unclear. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. six as a VUS, and one as likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jun 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;T;.

Eigen

Benign

-0.053

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.45

MVP

0.98

MPC

0.0087

ClinPred

0.18

GERP RS

1.3

Varity_R

0.18

gMVP

0.71

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