rs1800123

Positions:

chr7-117627712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.3659C>T(p.Thr1220Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11

Conservation

PhyloP100: -0.302

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 70 pathogenic changes around while only 7 benign (91%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25415435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3659C>T	p.Thr1220Ile	missense_variant	22/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3659C>T	p.Thr1220Ile	missense_variant	22/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.66-11372G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152126

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:

0.00154

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000999

AC:

AN:

250156

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000763

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000958

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:5

Uncertain significance, 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: PM2_SUP, PM3, PP4, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 1994	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2022	The p.T1220I variant (also known as c.3659C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3659. The threonine at codon 1220 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a 60 year old woman with a 10 year history of chronic lung disease (Ghanem N et al. Genomics. 1994;21(2):434-6) and in a 13 year old with gastrointestinal problems, elevated sweat chloride, and pancreatic sufficiency (Onay T et al. Hum Genet. 1998;102(2):224-30); however, a second disease-causing variant in trans was not described in either case. In addition, this alteration was reported in a child with pancreatitis who was also heterozygous for disease-causing variants in PRSS1 and SPINK1 (Xiao Y et al. J. Pediatr., 2017 12;191:158-163.e3). This amino acid position is poorly conserved in available vertebrate species, and I is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1220 of the CFTR protein (p.Thr1220Ile). This variant is present in population databases (rs1800123, gnomAD 0.09%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 7522211, 9272738, 9521595, 29173301, 32777524). ClinVar contains an entry for this variant (Variation ID: 7214). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.	Apr 28, 2018	- -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 11, 2020	The CFTR c.3659C>T; p.Thr1220Ile variant (rs1800123) is reported in the literature in individuals with a clinical diagnosis of cystic fibrosis or asthma (Ghanem 1994, Lazaro 1999, Onay 1998, Xiao 2017). This variant is also reported in ClinVar (Variation ID: 7214). This variant is found in the East Asian population with an allele frequency of 0.085% (17/19,904 alleles) in the Genome Aggregation Database. The threonine at codon 1220 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.40). Given the lack of clinical and functional data, the significance of the p.Thr1220Ile variant is uncertain at this time. References: Ghanem N et al. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994. 21(2):434-6. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999. 14(6):510-9. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998. 102(2):224-30. Xiao Y et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CFTR: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 02, 2024

Variant summary: CFTR c.3659C>T (p.Thr1220Ile) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250238 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.3659C>T has been reported in the literature in individuals affected with CFTR-related conditions without strong evidence of causality (Ghanem_1994, Lazaro_1999, Onay_1998, Bozdogan_2021, Li_2022, Luo_2021, Xiao_2017, Fujita_2022, Qiao_2018, Ni_2022). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7522211, 18716917, 9521595, 12651880, 9272738, 10571949, 26471113, 29173301, 33572515, 32777524, 35313924, 34931337, 35387941, 30060175). ClinVar contains an entry for this variant (Variation ID: 7214). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

The CFTR c.3659C>T variant is predicted to result in the amino acid substitution p.Thr1220Ile. This variant was detected in the compound heterozygous state in an individual with uncharacterized bronchopathy (Ghanem et al. 1994. PubMed ID: 7522211), and in the heterozygous state in a patient with gastrointestinal problems and a sweat test score of 75 mEq/l, a patient with asthma, and in a patient with pancreatitis alongside variants in the SPINK1 and PRSS1 genes (Onay et al. 1998. PubMed ID: 9521595; Lázaro et al. 1999. PubMed ID: 10571949; and Xiao et al. 2017. PubMed ID: 29173301, respectively). This variant is reported in 0.085% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.26

CADD

Benign

0.16

DANN

Benign

0.48

DEOGEN2

Uncertain

0.69

D;.;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.81

L;.;.;.;.

MutationTaster

Benign

0.00023

A;A

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.0

N;.;.;N;.

REVEL

Uncertain

0.40

Sift

Benign

0.58

T;.;.;T;.

Sift4G

Benign

0.30

T;.;.;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.15

MVP

0.71

MPC

0.0039

ClinPred

0.0058

GERP RS

-4.4

Varity_R

0.16

gMVP

0.57

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