7-117559594-T-G

Position:

chr7-117559594-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BP4BS2

The NM_000492.4(CFTR):c.1523T>G(p.Phe508Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,609,472 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign 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. F508L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00091 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7B:10

Conservation

PhyloP100: 7.54

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:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000492.4

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.28578582).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1523T>G	p.Phe508Cys	missense_variant	11/27	ENST00000003084.11
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.221+1139A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1523T>G	p.Phe508Cys	missense_variant	11/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000915

AC:

137

AN:

149752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.000486

GnomAD3 exomes

AF:

0.000937

AC:

232

AN:

247712

Hom.:

AF XY:

0.000903

AC XY:

121

AN XY:

133924

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000326

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.00135

AC:

1965

AN:

1459602

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

912

AN XY:

726240

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00167

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000914

AC:

137

AN:

149870

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

AN XY:

73370

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.000395

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00173

Gnomad4 OTH

AF:

0.000481

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000880

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000951

AC:

115

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:7Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 28, 2024	The p.F508C variant (also known as c.1523T>G), located in coding exon 11 of the CFTR gene, results from a T to G substitution at nucleotide position 1523. The phenylalanine at codon 508 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first detected in two healthy individuals who also carried the p.F508del mutation on the other chromosome; thus, the authors suggested a benign classification (Kobayashi K et al. Am. J. Hum. Genet., 1990 Oct;47:611-5). Subsequently, p.F508C was detected with another pathogenic mutation in 3 of 182 individuals with congenital bilateral absence of the vas deferens (CBAVD). This same study also described 5 individuals who were compound heterozygous with another pathogenic mutation in a cohort of 5938 individuals suspected to have CF. However, the frequency of the p.F508C variant in this suspected CF population did not significantly differ from that of their control population (Havasi V et al. Genet. Med., 2008 Dec;10:910-4). Functional studies determined that this substitution does not affect CFTR function, protein folding, or the transport of the protein to the cell membrane, but could affect ion channel function, particularly when co-occurring with another alteration (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Du K et al. Nat. Struct. Mol. Biol., 2005 Jan;12:17-25; Cui L et al. J. Physiol. (Lond.), 2006 Apr;572:347-58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 30, 2019	- -
Benign, no assertion criteria provided	literature only	OMIM	Oct 01, 1990	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Benign by Emory. Compund heterozygotes foe this variant and %508del variant were clinically normal, therefore this variant has been classified as benign by Kobayashi et al 1990. Frequency of the variant was higher in individuals with CBAVD (Havasi 2008). Phenotype does not meet reporting criteria. -

CFTR-related disorder

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -

not provided

Pathogenic:1Benign:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 09, 2020	The CFTR c.1523T>G; p.Phe508Cys variant (rs74571530) is reported in the literature in individuals affected with monosymptomatic CFTR-related disorders, such as congenital bilateral absence of the vas deferens or pancreatitis, who also carried an additional pathogenic variant on the opposite chromosome (Dork 1997, Havasi 2008, Meschede 1993, Palermo 2016). This variant has also been reported in asymptomatic individuals (Desgeorges 1994, Kobayashi 1990, Macek 1992), although this may be due to reduced penetrance of CFTR-related disorders. This variant is listed in ClinVar (Variation ID: 7126), and is present in the non-Finnish European population with an overall allele frequency of 0.18% (230/125858 alleles) in the Genome Aggregation Database. The phenylalanine at codon 508 is highly conserved, and computational programs (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered mildly pathogenic and not causative for classic cystic fibrosis. References: Desgeorges M et al. A healthy male with compound and double heterozygosities for delta F508, F508C, and M47OV in exon 10 of the cystic fibrosis gene. Am J Hum Genet. 1994 54(2):384-5. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 100(3-4):365-77. Havasi V et al. The role of the F508C mutation in congenital bilateral absence of the vas deferens. Genet Med. 2008 10(12):910-4. Kobayashi K et al. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 47(4):611-5. Macek M Jr et al. Missense variations in the cystic fibrosis gene: heteroduplex formation in the F508C mutation. Am J Hum Genet. 1992 Nov;51(5):1173-4. Meschede D et al. Compound heterozygosity for the delta F508 and F508C cystic fibrosis transmembrane conductance regulator (CFTR) mutations in a patient with congenital bilateral aplasia of the vas deferens. Am J Hum Genet. 1993 Jul;53(1):292-3. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CFTR: BP2, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2020	- -

Hereditary pancreatitis

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 20, 2022	ACMG classification criteria: PP3 supporting -

Obstructive azoospermia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Reproductive Genetics, University of Münster

Aug 23, 2021

- -

Infertility disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;.;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.6

M;.;.;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.8

D;.;.;D;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.96

MVP

1.0

MPC

0.013

ClinPred

0.083

GERP RS

5.5

Varity_R

0.94

gMVP

0.98

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

Other links and lift over