7-117664821-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000492.4(CFTR):c.4097T>C(p.Ile1366Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,030 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1366N) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:8
• Conservation: PhyloP100: 7.52

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117664821-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 551822.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 7-117664821-T-C is Pathogenic according to our data. Variant chr7-117664821-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526019.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=5, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.4097T>C	p.Ile1366Thr	missense_variant	25/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.4097T>C	p.Ile1366Thr	missense_variant	25/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000119 AC: 3 AN: 251286 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461736 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 01, 2022	The p.I1366T variant (also known as c.4097T>C), located in coding exon 25 of the CFTR gene, results from a T to C substitution at nucleotide position 4097. The isoleucine at codon 1366 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a subject with congenital bilateral absence of the vas deferens (CBAVD) and in one ostensibly healthy individual (Le Maréchal C et al. Hum. Genet., 2001 Apr;108:290-8; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). Another alteration affecting the same amino acid, p.I1366N (c.4097T>A), has been reported in a cystic fibrosis (CF) cohort (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). 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. -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Jan 19, 2023	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM5_STR, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	This sequence change replaces isoleucine with threonine at codon 1366 of the CFTR protein (p.Ile1366Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs200955612, ExAC 0.009%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas defense (PMID: 21520337). ClinVar contains an entry for this variant (Variation ID: 526019). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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, criteria provided, single submitter	clinical testing	Counsyl	Jun 02, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 13, 2020	The CFTR c.4097T>C; p.Ile1366Thr variant (rs200955612) is reported in the literature in the heterozygous state in individuals affected with congenital bilateral absence of the vas deferens and also in healthy carriers (Le Marechal 2001, Steiner 2011). This variant is reported in ClinVar (Variation ID: 526019), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 1366 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.4097T>A; p.Ile1366Asn; c.4096A>T; p.Ile1366Phe) have been reported in individuals with cystic fibrosis (see link to CFTR2 database, Arslan 2020). However, given the lack of clinical and functional data, the significance of the p.Ile1366Thr variant is uncertain at this time. References: Link to CFTR2 database: https://cftr2.org/ Arslan AB et al. A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype-c.4096A?>?T. J Pediatr Genet. 2020;9(1):40-43. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001;108(4):290-298. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2012 Feb;33(2):456. Hum Mutat. 2011;32(8):912-920. -

CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 10, 2023

Variant summary: CFTR c.4097T>C (p.Ile1366Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 1.6e-05 in 252084 control chromosomes (gnomAD, Steiner_2011, Berg_2013). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4097T>C has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (Steiner_2011) and Cystic Fibrosis (Feuillet_Fieux_2002, Raraigh_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants impacting codon 1366 have been described as pathogenic (c.4097T>A [p.Ile1366Asn] ClinVar:551822) or of uncertain significance (c.4096A>T [p.Ile1366Phe] ClinVar:632751). Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.99
MVP		1.0
MPC		0.015
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200955612; hg19: chr7-117304875;