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).

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:5B:16O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1
In a helix (size 27) in uniprot entity CFTR_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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: {Uncertain_significance=2, Benign=6, Likely_benign=8, 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 rank MANE Protein UniProt
CFTRNM_000492.4 linkc.224G>A p.Arg75Gln missense_variant Exon 3 of 27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.224G>A p.Arg75Gln missense_variant Exon 3 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

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:5Benign:16Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:2Benign:6
Jan 29, 2018
CFTR-France
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

the variant does not result in CFTR-RD neither -

May 18, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 06, 2019
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 22, 2014
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 24, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:5
Feb 22, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 28, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 16, 2017
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 03, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:3
Oct 02, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 22, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CFTR: BS1, BS2 -

Sep 07, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

CFTR-related disorder Uncertain:1Benign:1
Feb 01, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

May 18, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Lung disease, non-specific Uncertain:1
May 14, 2015
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Abnormality of the pancreas Other:1
-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

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
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