7-117479869-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000546407.1(CFTR):n.166+4061G>T variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 593,708 control chromosomes in the GnomAD database, including 3 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 0.0039 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00062 ( 1 hom. )

Consequence

CFTR
ENST00000546407.1 intron, non_coding_transcript

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.54

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 7-117479869-G-T is Benign according to our data. Variant chr7-117479869-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51031.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=2}.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	Effect	TSL
CFTR	ENST00000546407.1 linkuse as main transcript	n.166+4061G>T	intron_variant, non_coding_transcript_variant	1
CFTR	ENST00000446805.2 linkuse as main transcript	c.-191+175G>T	intron_variant	4
CFTR	ENST00000673785.1 linkuse as main transcript	c.-406+14038G>T	intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

587

AN:

151620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00237

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:

0.00242

GnomAD4 exome

AF:

0.000620

AC:

274

AN:

441970

Hom.:

Cov.:

AF XY:

0.000534

AC XY:

125

AN XY:

233892

show subpopulations

Gnomad4 AFR exome

AF:

0.0155

Gnomad4 AMR exome

AF:

0.00138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000756

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00391

AC:

593

AN:

151738

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

266

AN XY:

74148

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.00237

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:

0.00239

Alfa

AF:

0.000666

Hom.:

Bravo

AF:

0.00464

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Describes a nucleotide substitution 226 basepairs upstream of the ATG translational start site in the 5' untranslated region (UTR); Identified in individuals with cystic fibrosis in published literature, but in whom a second CFTR variant was either not detected or not specified (Romey 1999, des Georges 2008, Zeiger 2020); Published functional studies demonstrate decreased Sp1 and USF DNA-binding and decreased transcriptional activity in one study that utilized a core promoter construct, but the associated transcriptional activity was not significantly different from wild type in a second study that utilized a full-length promoter construct (Taulan 2007, Ott 2012); Also known as c.-94G>T; This variant is associated with the following publications: (PMID: 12939925, 26656651, 11168023, 31665830, 18832460, 21948798, 10204861, 17678620, 37313453) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2023	In the published literature, this variant has been reported in individuals with cystic fibrosis (PMIDs: 31665830 (2020), 18832460 (2008), 11168023 (2001), 10204861 (1999)). Functional studies indicate this variant may impact promoter activity but not at a significant difference from the wild type (PMIDs: 17678620 (2007), 21948798 (2012)). The frequency of this variant in the general population, 0.014 (117/8656 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2021	- -

Cystic fibrosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 12, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Apr 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

Cadd

Benign

Dann

Benign

0.81

Splicing

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