chr7-117479869-G-T

Position:

• chr7-117479869-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000446805.2(CFTR):​c.-191+175G>T variant causes a intron 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 ENST00000446805.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 1.54

Genes affected

CFTR (HGNC:):

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 -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: {Likely_benign=2, Uncertain_significance=4, Benign=1}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.117479869G>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000546407.1	n.166+4061G>T		intron_variant		1
CFTR	ENST00000673785.1	c.-406+14038G>T		intron_variant				ENSP00000501235.1
CFTR	ENST00000446805.2	c.-191+175G>T		intron_variant		4		ENSP00000417012.1

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 587 AN: 151620 Hom.: 2 Cov.: 31

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.: 1 Cov.: 3 AF XY: 0.000534 AC XY: 125 AN XY: 233892

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.: 2 Cov.: 31 AF XY: 0.00359 AC XY: 266 AN XY: 74148

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.: 0

Bravo AF: 0.00464

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 04, 2024	The CFTR c.-266G>T variant has been reported in the published literature in individuals with cystic fibrosis (CF) (PMIDs: 31665830 (2020), 18832460 (2008), 11168023 (2001), 10204861 (1999)). Functional studies indicate this variant may impact promoter activity but further evidence is needed to understand the global impact of this variant on disease (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	- -
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	GeneDx	Apr 11, 2024	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 (PMID: 17678620, 21948798); Identified in individuals with cystic fibrosis in published literature, but in whom a second CFTR variant was either not detected or not specified (PMID: 10204861, 31665830, 18832460); Describes a nucleotide substitution 226 basepairs upstream of the ATG translational start site in the 5' untranslated region (UTR); Also known as c.-94G>T; This variant is associated with the following publications: (PMID: 12939925, 26656651, 11168023, 31665830, 18832460, 21948798, 10204861, 37313453, 17678620) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2018	- -

Cystic fibrosis Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2023	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.81

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73717525; hg19: chr7-117119923;