rs76179227

Positions:

• chr7-117665577-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.4242+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,488,290 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (22 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.944

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-117665577-A-G is Benign according to our data. Variant chr7-117665577-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117665577-A-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 22 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	UniProt
CFTR	NM_000492.4	c.4242+13A>G		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.4242+13A>G		intron_variant		1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00344 AC: 860 AN: 250278 Hom.: 5 AF XY: 0.00355 AC XY: 480 AN XY: 135236

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.000741

Gnomad NFE exome AF: 0.00456

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00413 AC: 5511 AN: 1335936 Hom.: 22 Cov.: 21 AF XY: 0.00407 AC XY: 2732 AN XY: 671918

Gnomad4 AFR exome AF: 0.000648

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00164

Gnomad4 FIN exome AF: 0.000957

Gnomad4 NFE exome AF: 0.00459

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74502

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00580 Hom.: 0

Bravo AF: 0.00296

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:7

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 24, 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	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 26, 2019	- -
Benign, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: BS2, BS3, BP4 -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2017	c.4242+13A>G in intron 26 of CFTR: This variant is not expected to have clinical significance because it has been identified in 1.6% (159/10116) of Ashkenazi Je wish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs76179227). It was also identified in 5 homozygotes in gn omAD. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2016	Variant summary: The CFTR c.4242+13A>G variant involves the alteration of a non-conserved intronic nucleotide at a position not widely known to affect normal splicing. One in silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict the variant not to affect splicing, and this prediction is supported by a minigene splicing assay showing no abnormal RNA products from a minigene containing this intronic variant. This variant was found in 424/120694 control chromosomes (including 1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0051196 (333/65044). This frequency is less than the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), and it cannot be ruled out that the homozygote could be affected since the ExAC cohort is a general population cohort rather than a healthy or disease-free cohort. Although this variant is found at a frequency less than the most common pathogenic CFTR variant, DeltaF508 (allele frequency in ExAC of 823/121296), c.4242+13A>G is found at a frequency greater than 2-fold higher than the second most common pathogenic CFTR variant in ExAC, c.350G>A (p.Arg117His; 185/120360), highly suggesting that c.4242+13A>G is not pathogenic.Although the variant has been found in patients reported in the literature, there are no reports that show the variants clear-cut causal role in CF and/or CBAVD. In other CFTR-RD phenotypes (asthma, DB, and COPD), this variant was observed at similar frequencies in cases and controls, supporting the notion that it is not a risk factor for these milder phenotypes either. To our knowledge, there was only one report of the variant co-occurring with a pathogenic variant, c.5T_TG11, in a diffuse bronchiectasis patient; however, c.-1043dupT (not in ClinVar and not yet internally classified) was also identified in this patient, phase of these variants was not specified, segregation studies were not performed, and authors consider the variant of interest to be a polymorphism since functional studies showed no effect on splicing (Bergougnoux_JCF_2015). Additionally, UMD reports the variant as a complex allele with c.2538G>A (p.Trp846X) and c.1521_1523delCTT (p.Phe508del) on the other allele in an individual with CF (unpublished reference), suggesting that the variant of interest is not causative in this patient. Furthermore, multiple papers as well as Emory Genetics lab via ClinVar and SickKids report the variant as a benign polymorphism. Taken together, this intronic CFTR variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CFTR: BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 31, 2021	- -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

May 17, 2021

- -

CFTR-related disorder Benign:1

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs76179227; hg19: chr7-117305631;