rs121909017

chr7-117559546-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 7.44

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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/exons	MANE	UniProt
CFTR	NM_000492.4	c.1475C>T	p.Ser492Phe	missense_variant	11/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.221+1187G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1475C>T	p.Ser492Phe	missense_variant	11/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251334 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135842

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: 4 AN: 1459224 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726106

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 22, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 08, 2023	This variant is present in population databases (rs121909017, gnomAD 0.003%). 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870, 26864378, 30046002). 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. ClinVar contains an entry for this variant (Variation ID: 7155). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 15365999, 16189704, 21097845, 27086061). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 10, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 22, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2022	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. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 09, 2020

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.76	N;.;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.60	T
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	D
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

Other links and lift over

dbSNP: rs121909017; hg19: chr7-117199600; COSMIC: COSV50068549; COSMIC: COSV50068549;