rs1800076

chr7-117509093-G-Achr7-117509093-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:14 O:2
• Conservation: PhyloP100: 7.71

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]

ACMG classification

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, Uncertain_significance=3, not_provided=2, Likely_benign=6}. 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	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	c.224G>A	p.Arg75Gln	missense_variant	3/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2830 AN: 152172 Hom.: 44 Cov.: 33

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

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

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

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:6 Benign:14 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2 Benign:6

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

not provided Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CFTR: BS1, BS2 -
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	- -

not specified Benign:4

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

CFTR-related disorder Uncertain:1 Benign:1

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

Hereditary pancreatitis Benign:1 Other:1

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

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	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

Other links and lift over

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