rs138025486

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000492.4(CFTR):c.4243-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,612,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CFTR
NM_000492.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 1.36

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 7-117666888-A-G is Benign according to our data. Variant chr7-117666888-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439084.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4243-20A>G		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.4243-20A>G		intron_variant		1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000789

AC:

120

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000212

AC:

AN:

249550

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135020

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1460214

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152206

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00289

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000897

Hom.:

Bravo

AF:

0.000960

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2023	- -

Cystic fibrosis

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2023	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 06, 2021

Variant summary: CFTR c.4243-20A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/3 computational tools predict no significant impact on normal splicing, which has been confirmed by minigene assay (Leman_2020). The variant allele was found at a frequency of 0.00028 in 280948 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. This frequency is lower than the maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) (0.013), however, prevalence of CF is known to be lower in Africans (see e.g. PMID 9506637), therefore this variant might still represent a benign polymorphism. c.4243-20A>G has been reported in the literature in heterozygosity in individuals affected with various conditions, including chronic- or recurrent pancreatitis, Pseudomonas pneumonia, idiopathic bronchiectasis and asthma (Keiles_2006, Fajac_2008, Crespo-Lessmann_2021). The variant was also identified in individuals with a positive newborn screen result (Ridge_2013, Lefterova_2016, Salinas_2017, Kasi_2020), however, one of these individuals also carried a common disease variant (F508del; phase not specified) and was reportedly asymptomatic with a normal sweat chloride level (Kasi_2020), whereas the other individual carried two other variants c.2988+1G>A, c.224G>T (p.Arg75Leu) (classified internally as pathogenic for CF, and VUS-possibly pathogenic for CBAVD, respectively), which could potentially explain the positive newborn screen finding (Ridge_2013). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. In addition, this variant was also present in one internal sample, together with 5T_TG11 (internally classified as pathogenic for CBAVD) and c.224G>T (p.Arg75Leu), indicating the variant of interest may possibly be a benign variant. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 25, 2020

- -

CFTR-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

Cadd

Benign

Dann

Benign

0.88

La Branchor

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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