7-117642457-C-T

Position:

chr7-117642457-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.3737C>T(p.Thr1246Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,613,436 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1246T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 5.71

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 7-117642457-C-T is Pathogenic according to our data. Variant chr7-117642457-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117642457-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3737C>T	p.Thr1246Ile	missense_variant	23/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3737C>T	p.Thr1246Ile	missense_variant	23/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.65+4894G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

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:

0.00000398

AC:

AN:

250992

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135636

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461332

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74290

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

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 08, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1246 of the CFTR protein (p.Thr1246Ile). This variant is present in population databases (rs397508600, gnomAD 0.0009%). This missense change has been observed in individuals with cystic fibrosis, and intermediate sweat chloride results (PMID: 10923036, 19318346, 20538955, 22678879, 28129813). ClinVar contains an entry for this variant (Variation ID: 53799). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	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: PS3_SUP, PM2_SUP, PM3_STR, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2022	Variant summary: CFTR c.3737C>T (p.Thr1246Ile) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding (IPR003439) and AAA+ ATPase (IPR003593) domains 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 4e-06 in 250992 control chromosomes (gnomAD). c.3737C>T has been reported in the literature as a compound heterozygous genotype (mostly in trans with the known pathogenic variant p.Phe508del) in multiple individuals affected with Non-Classic Cystic Fibrosis related phenotypes and has been linked to varying clinical consequences; sweat chloride values were reported to be in the intermediate range for at least some of these individuals (example: Claustres_2000, Goubau_2009, El-Seedy_2012, Sosnay_2017_McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal CFTR activity (Han_2018, Raraigh_2018). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as VUS (n=2), likely pathogenic (n=2) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic, with varying clinical consequences. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Aug 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 27, 2020	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 31, 2022	The p.T1246I pathogenic mutation (also known as c.3737C>T), located in coding exon 23 of the CFTR gene, results from a C to T substitution at nucleotide position 3737. The threonine at codon 1246 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with another CFTR alteration in several individuals with cystic fibrosis or CFTR-related disorders (Claustres M et al. Hum. Mutat., 2000;16:143-56; Goubau C et al. Thorax, 2009 Aug;64:683-91; Sermet-Gaudelus I et al. Am. J. Respir. Crit. Care Med., 2010 Oct;182:929-36; Masica DL et al. Hum. Mol. Genet., 2015 Apr;24:1908-17). This position has been shown to be important in binding ATP for chloride channel gating, however, the T1246I alteration was not specifically evaluated (Vergani P et al. Nature, 2005 Feb;433:876-80). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 03/29/2022). In CFBE cells, this variant showed reduced CFTR function compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3(14):pii 121159). The p.T1246I alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

CFTR-related disorder

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 18, 2024	The CFTR c.3737C>T variant is predicted to result in the amino acid substitution p.Thr1246Ile. This variant, along with a second CFTR variant, has been reported in individuals with cystic fibrosis (CF) and cystic fibrosis-related disorders (CF-RD), including congenital bilateral absence of the vas deferens (Table 4, Claustres et al. 2000. PubMed ID: 10923036; Table 1, El-Seedy et al. 2012. PubMed ID: 22678879; Sosnay et al. 2017. PubMed ID: 28129813; CFTR-France database, https://cftr.iurc.montp.inserm.fr/cgi-bin/affiche.cgi?variant=c.3737C%3ET). This variant has also been reported in in the CFTR2 Database in more than 20 patients as a variant of varying clinical consequence and has been reported in the heterozygous state in a study of individuals with COPD or asthma (Supplementary Table 1, Saferali et al. 2022. PubMed ID: 34996830; https://cftr2.org/mutation/general/T1246I/). In vitro experimental studies suggest this variant reduces CFTR function to 10%–20% compared to control (Raraigh et al. 2018. PubMed ID: 29805046; Han et al. 2018. PubMed ID: 30046002). An alternate nucleotide substitution affecting the same amino acid (p.Thr1246Ala), has been reported in an individual with male infertility (Table 2, Li et al. 2022. PubMed ID: 34931337). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. Taken together, the c.3737C>T (p.Thr1246Ile) variant is interpreted as likely pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 18, 2021	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 09, 2020

The CFTR c.3737C>T; p.Thr1246Ile variant (rs397508600) is reported in the literature in the compound heterozygous state with a different pathogenic variant in individuals affected with cystic fibrosis, a CFTR-related disorder, or borderline sweat chloride levels with no other significant symptoms (Claustres 2000, El-Seedy 2012, Goubau 2009, Masica 2015, Sermet-Gaudelus 2010, Sosnay 2017). This variant is reported in ClinVar (Variation ID: 53799), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1246 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses of the variant protein demonstrate 13% of wild-type function, consistent with an intermediate effect (Raraigh 2018). Based on available information, this variant is considered to be likely pathogenic with variable clinical consequences. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2. References: Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-156. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012;33(11):1557-1565. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009;64(8):683-691. Masica DL et al. Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity. Hum Mol Genet. 2015;24(7):1908-1917. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018;102(6):1062-1077. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010;182(7):929-936. Sosnay PR, White TB, Farrell PM, et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017;181S:S52-S57.e2. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.0

D;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

0.98

D;.;.

Vest4

0.96

MutPred

0.68

Loss of disorder (P = 0.0226);.;.;

MVP

1.0

MPC

0.010

ClinPred

0.99

GERP RS

5.2

Varity_R

0.98

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

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