7-117504290-C-T

Position:

chr7-117504290-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

The ENST00000003084.11(CFTR):c.91C>T(p.Arg31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,611,884 control chromosomes in the GnomAD database, including 9 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. R31L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 9 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:8

Conservation

PhyloP100: 3.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 33 pathogenic changes around while only 4 benign (89%) in ENST00000003084.11

BP4

Computational evidence support a benign effect (MetaRNN=0.011254132).

BP6

Variant 7-117504290-C-T is Benign according to our data. Variant chr7-117504290-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35893.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=9}. Variant chr7-117504290-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 9 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.91C>T	p.Arg31Cys	missense_variant	2/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.91C>T	p.Arg31Cys	missense_variant	2/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00168

AC:

421

AN:

250938

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.00544

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00154

AC:

2241

AN:

1459662

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1112

AN XY:

726340

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0119

Gnomad4 EAS exome

AF:

0.00702

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152222

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.00483

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00167

AC:

203

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 15, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Jul 26, 2023	This variant was classified based on the report of 1 patient with a clinically confirmed diagnosis of cystic fibrosis in the context of re-classifying variants in the German Cystic Fibrosis Registry (Muko e.V.). Patients have not been seen personally, but only reports were evaluated. Criteria applied:PP3, PM5_STR, BP6, BS3_SUP, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 26, 2023	The frequency of this variant in the general population, 0.0015 (191/128724 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with mild cystic fibrosis (CF) (PMID: 9272738 (1997)), pancreatitis (PMID: 12120234 (2001), 25033378 (2014), 25383785 (2015), 25492507 (2015), 25869325 (2015), 28544683 (2017)), and bronchiectasis (PMID: 7522211 (1994), 28544683 (2017), 29997923 (2018)). The variant has also been reported in unaffected individuals (PMID: 23514810 (2013), 25033378 (2014), 29997923 (2018)), including an unaffected individual in a homozygous state (PMID: 7522211 (1994)). The variant does not prevent chloride conduction by the CFTR protein in functional studies (PMID: 25824995 (2015)), but it has been reported as causing reduced CFTR protein activity by enhancing endocytosis of the CFTR protein (PMID: 16339147 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	The CFTR c.91C>T; p.Arg31Cys variant (rs1800073) is reported in individuals with idiopathic pancreatitis (Bernardino 2000, Gomez-Lira 2001), oligospermia (Gallati 2009), bronchiectasis (Guan 2018), mild pulmonary disorders (Ghanem 1994), and congenital absence of the vas deferens (Fang 2022). Although initial functional studies suggested a defect in CFTR processing and chloride transport activity (Jurkuvenaite 2006), subsequent studies indicated no defects (Sosnay 2013). In addition, the variant has been reported as a homozygote in an asymptomatic individual (Ghanem 1994) and was shown not to be enriched in individuals diagnosed with pancreatitis (LaRusch 2014). This variant is reported in ClinVar (Variation ID: 35893), and found in the general population with an overall allele frequency of 0.2% (447/276630 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.669). However, another variant at this codon (p.Arg31Leu) has been reported in an individual with elevated sweat chloride levels (Zielenski 1995) and exhibited 56% of wildtype chloride channel activity in functional assays (Raraigh 2018). Due to the conflicting information regarding this variant, its clinical significance is uncertain at this time. References: Bernardino AL et al. Molecular analysis in Brazilian cystic fibrosis patients reveals five novel mutations. Genet Test. 2000;4(1):69-74. PMID: 10794365 Fang J et al. Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations. Front Genet. 2022 Nov 9;13:1035468. PMID: 36437957. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. PMID: 20021716 Ghanem N et al. Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics. 1994 May 15;21(2):434-6. PMID: 7522211 Gomez-Lira M et al. CFTR and cationic trypsinogen mutations in idiopathic pancreatitis and neonatal hypertrypsinemia. Pancreatology. 2001;1(5):538-42. PMID: 12120234 Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923 Jurkuvenaite A et al. Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis. J Biol Chem. 2006 Feb 10;281(6):3329-34. PMID: 16339147 LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 Jul 17;10(7):e1004376. PMID: 25033378 Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870 Zielenski J et al. Identification of six mutations (R31L, 441delA, 681delC, 1461ins4, W1089R, E1104X) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1995;5(1):43-7. PMID: 7537150 -

not specified

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2016	Variant summary: c.91C>T affects a conserved nucleotide, resulting in amino acid change from Arg to Cys. 5/5 in-silico tools predict damaging outcome. This variant was found in 214/124456 control chromosomes at a frequency of 0.0017195, including 1 homozygous occurrence. This frequency does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603) for non-classic CF. This variant has been found in patients with atypical CF, ICP and asthma-like bronchopathy. Variant was also found in healthy individuals, including 1 compound heterozygote with F508del with no symptoms suggestive of CF, 1 homozygous asymptomatic 6 y.o. child with family member presented with asthma-like bronchopathy (Ghanem_1994) and one homozygote in ExAC database. CFTR2 database classified this variant as non-CF-casuing based on clinical and functional data (Sosnay_2013). A case-control study including more than 2000 samples showed odds ratio of this variant associated with pancreatitis was 0.42, suggesting this variant does not increase the risk to develop pancreatitis (LaRusch_2014). Taken together, this variant was classified as Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2017	The R31C variant in the CFTR gene was first identified in the homozygous state in an asymptomatic individual and reported as a benign polymorphism (Ghanem et al., 1994). Other publications have reported this variant in association with disseminated bronchiectasis (Girodon et al., 1997), idiopathic pancreatitis (Gomez Lira et al., 2001), and oligospermia (Gallati et al., 2009), though a second CFTR variant was not identified in these cases. The R31C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R31C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R31L) was identified in an adult woman with pulmonary symptoms but normal pulmonary function, normal pancreatic function, and repeated abnormal sweat chloride levels (mean value 90.9 mmol/L); no second CFTR variant was identified (Zielenski et al., 1995). Functional studies performed show that R31C affects protein biogenesis, although the defect is not complete (Jurkuvenaite et al., 2006). While the R31C variant has been deemed not to be cystic fibrosis-causing (Sosnay et al., 2013), it is possible this variant may have reduced penetrance in association with CF-related disorders. We interpret R31C as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

CFTR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

Hereditary pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;.;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.8

L;.;.;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.8

N;.;.;N;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.012

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.89

MVP

0.99

MPC

0.0038

ClinPred

0.031

GERP RS

5.7

Varity_R

0.23

gMVP

0.77

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