rs1800076

Positions:

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

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]

CFTR links:

Genome browser will be placed here

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: {Likely_benign=6, Uncertain_significance=3, Benign=6, 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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.224G>A	p.Arg75Gln	missense_variant	3/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.224G>A	p.Arg75Gln	missense_variant	3/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2830

AN:

152172

Hom.:

Cov.:

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.:

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.:

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.:

Cov.:

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:

ESP6500EA

AF:

0.0308

AC:

265

ExAC

AF:

0.0153

AC:

1863

Asia WGS

AF:

0.00318

AC:

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 provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	This 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, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 06, 2023	The 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 submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CFTR: BS1, BS2 -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2014	- -

CFTR-related disorder

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Feb 01, 2022	- -
Likely benign, 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. 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. -

Hereditary pancreatitis

Benign:1Other:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 18, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Lung disease, non-specific

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

May 14, 2015

- -

Abnormality of the pancreas

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, 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

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

D;.;.;T;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.6

L;.;.;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

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

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.

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