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GeneBe

rs1800076

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000492.4(CFTR):c.224G>A(p.Arg75Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,611,610 control chromosomes in the GnomAD database, including 1,043 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. R75L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 44 hom., cov: 33)
Exomes 𝑓: 0.031 ( 999 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

7
6
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:14O:2

Conservation

PhyloP100: 7.71
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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, 14 uncertain in NM_000492.4
BP4
Computational evidence support a benign effect (MetaRNN=0.011586249).
BP6
Variant 7-117509093-G-A is Benign according to our data. Variant chr7-117509093-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35839.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=6, Uncertain_significance=3, not_provided=2}. Variant chr7-117509093-G-A is described in Lovd as [Benign]. Variant chr7-117509093-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2830/152290) while in subpopulation NFE AF= 0.0342 (2325/68014). AF 95% confidence interval is 0.033. There are 44 homozygotes in gnomad4. There are 1183 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 44 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.224G>A p.Arg75Gln missense_variant 3/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.224G>A p.Arg75Gln missense_variant 3/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.0186
AC:
2830
AN:
152172
Hom.:
44
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00741
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00844
Gnomad ASJ
AF:
0.00548
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00255
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.0342
Gnomad OTH
AF:
0.00670
GnomAD3 exomes
AF:
0.0154
AC:
3874
AN:
250966
Hom.:
59
AF XY:
0.0153
AC XY:
2080
AN XY:
135648
show subpopulations
Gnomad AFR exome
AF:
0.00597
Gnomad AMR exome
AF:
0.00709
Gnomad ASJ exome
AF:
0.00357
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00203
Gnomad FIN exome
AF:
0.00437
Gnomad NFE exome
AF:
0.0285
Gnomad OTH exome
AF:
0.0173
GnomAD4 exome
AF:
0.0313
AC:
45647
AN:
1459320
Hom.:
999
Cov.:
29
AF XY:
0.0299
AC XY:
21694
AN XY:
726240
show subpopulations
Gnomad4 AFR exome
AF:
0.00493
Gnomad4 AMR exome
AF:
0.00731
Gnomad4 ASJ exome
AF:
0.00463
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00208
Gnomad4 FIN exome
AF:
0.00454
Gnomad4 NFE exome
AF:
0.0386
Gnomad4 OTH exome
AF:
0.0295
GnomAD4 genome
AF:
0.0186
AC:
2830
AN:
152290
Hom.:
44
Cov.:
33
AF XY:
0.0159
AC XY:
1183
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.00739
Gnomad4 AMR
AF:
0.00843
Gnomad4 ASJ
AF:
0.00548
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00255
Gnomad4 NFE
AF:
0.0342
Gnomad4 OTH
AF:
0.00663
Alfa
AF:
0.0260
Hom.:
120
Bravo
AF:
0.0187
TwinsUK
AF:
0.0353
AC:
131
ALSPAC
AF:
0.0475
AC:
183
ESP6500AA
AF:
0.00976
AC:
43
ESP6500EA
AF:
0.0308
AC:
265
ExAC
AF:
0.0153
AC:
1863
Asia WGS
AF:
0.00318
AC:
11
AN:
3472
EpiCase
AF:
0.0323
EpiControl
AF:
0.0296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:14Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:2Benign:6
Benign, no assertion criteria providedclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 22, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMay 18, 2021- -
Benign, criteria provided, single submittercurationCFTR-FranceJan 29, 2018the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 01, 2014This alteration is classified as 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, no assertion criteria providedclinical testingNatera, Inc.Aug 06, 2019- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenFeb 01, 2022- -
Uncertain significance, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
not provided Uncertain:2Benign:2
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024CFTR: BS1, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 06, 2023The CFTR c.224G>A (p.Arg75Gln) variant has been reported in the published literature in individuals affected with pancreatitis (PMID: 25033378 (2014), 27555793 (2016), 32447501 (2021), 35096544 (2022)), chronic obstructive pulmonary disease (PMID: 15463907 (2004), 34996830 (2022)), rheumatoid arthritis and/or diffuse bronchiectasis (PMID: 21131649 (2011), 25797027 (2015)), and idiopathic infertility (PMID: 32155011 (2020)). Functional studies show the variant as having acceptable (PMID: 18306312 (2008), 25033378 (2014)) or reduced chloride conductance activity (PMID: 23974870 (2013), 35418593 (2022)), reduced mRNA expression and processing (PMID: 25797027 (2015)), and defects in bicarbonate conductance (PMID: 25033378 (2014)). However, other studies report the variant CFTR protein is processed and glycosylated in a manner comparable to the wild-type (PMID: 18306312 (2008), 23974870 (2013), 25033378 (2014), 35418593 (2022)). The frequency of this variant in the general population, 0.039 (1980/50646 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 28, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 07, 2017- -
not specified Benign:4
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 03, 2016- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 28, 2014- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 16, 2017- -
CFTR-related disorders Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenFeb 01, 2022- -
Hereditary pancreatitis Benign:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Likely benign, criteria provided, single submittercurationSema4, Sema4May 18, 2021- -
Lung disease, non-specific Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalMay 14, 2015- -
Abnormality of the pancreas Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpretted as Uncertain significance and reported on 02-10-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.065
T
BayesDel_noAF
Pathogenic
0.36
Cadd
Pathogenic
30
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.62
D;.;.;T;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;D;D;D;D
MetaRNN
Benign
0.012
T;T;T;T;T
MetaSVM
Uncertain
0.47
D
MutationAssessor
Benign
1.6
L;.;.;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-2.2
N;.;.;N;.
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0050
D;.;.;D;.
Sift4G
Pathogenic
0.0
D;.;.;D;.
Polyphen
1.0
D;.;.;.;.
Vest4
0.33
MPC
0.0066
ClinPred
0.013
T
GERP RS
5.7
Varity_R
0.80
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs1800076; hg19: chr7-117149147; COSMIC: COSV50052290; COSMIC: COSV50052290; API