rs121909017

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.1475C>T(p.Ser492Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,224 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 Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 7.44

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:

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.977

PP5

Variant 7-117559546-C-T is Pathogenic according to our data. Variant chr7-117559546-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7155.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559546-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1475C>T	p.Ser492Phe	missense_variant	Exon 11 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 link	n.221+1187G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1475C>T	p.Ser492Phe	missense_variant	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251334

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135842

show subpopulations

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:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459224

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 22, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1475C>T (p.Ser492Phe) 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 8e-06 in 251334 control chromosomes (gnomAD). c.1475C>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Wine_2001, Alper_2004, McGinniss_2005, Sheridan_2011, Lakeman_2008, Scotet_2002). These data indicate that the variant is very likely to be associated with disease. Functional study, van Goor_2013, found the variant to significantly impede baseline chloride transport and mature CFTR protein production. Three ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 24, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S492F pathogenic mutation (also known as c.1475C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1475. The serine at codon 492 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation was first reported in a child diagnosed with pancreatic sufficient cystic fibrosis (CF), but the other mutation was not described (Férec C et al. Nat. Genet., 1992 Jun;1:188-91). It was also reported in an individual with pancreatic insufficient CF who also carried a frameshift alteration (Alper OM et al. Hum. Mutat., 2004 Oct;24:353). An individual with this mutation in conjunction with p.F508del presented with elevated sweat chloride levels, congenital absence of the vas deferens (CBAVD), and pancreatic sufficiency (Sheridan MB et al. J. Med. Genet., 2011 Apr;48:235-41). This mutation resulted in abnormal protein expression and no chloride transport in vitro (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Mar 10, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 22, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 492 of the CFTR protein (p.Ser492Phe). This variant is present in population databases (rs121909017, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 15365999, 16189704, 21097845, 27086061). ClinVar contains an entry for this variant (Variation ID: 7155). 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 not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870, 26864378, 30046002). For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

CFTR-related disorder

Pathogenic:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.1475C>T variant is predicted to result in the amino acid substitution p.Ser492Phe. This variant has been repeatedly reported to be causative for cystic fibrosis (see for example Férec et al. 1992. PubMed ID: 1284639; Sosnay. 2013. PubMed ID: 23974870). Functional studies show that the p.Ser492Phe substitution impacts normal protein function (Van Goor et al. 2014. PubMed ID: 23891399). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jul 09, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1475C>T; p.Ser492Phe variant (rs121909017) is reported in the literature in multiple individuals diagnosed with cystic fibrosis (Ferec 1992, Wine 2001, Sheridan 2011), often associated with pancreatic sufficiency (Sosnay 2013, CFTR2 database). Functional analyses of the variant protein indicate a defect in CFTR processing, resulting in the absence of chloride transport activity (Sosnay 2013, Van Goor 2014). This variant is reported in ClinVar (Variation ID: 7155), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at residue 492 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the above information, the p.Ser492Phe variant is classified as pathogenic. References: CFTR2 database: http://cftr2.org/ Ferec C et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 1(3):188-91. Sheridan M et al. CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 2011 48(4):235-41. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. Wine J et al. Comprehensive mutation screening in a cystic fibrosis center. Pediatrics. 2001 107(2):280-6. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Jan 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

0.76

N;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.5

D;.;.;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.019

D;.;.;D;.

Sift4G

Benign

0.090

T;.;.;T;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.86

MutPred

0.90

Loss of catalytic residue at S492 (P = 0.0028);.;.;.;.;

MVP

1.0

MPC

0.011

ClinPred

0.92

GERP RS

5.5

Varity_R

0.85

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.45

Position offset: 5

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