rs181008242

Variant names:

• chr7-117479283-T-G
• rs181008242
• ENST00000546407.1:n.166+3475T>G

Variant summary

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

The ENST00000446805(CFTR):​c.-486T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 152,176 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 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR ENST00000446805 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: -0.700

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 7-117479283-T-G is Benign according to our data. Variant chr7-117479283-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51029.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000546407.1	n.166+3475T>G		intron_variant	Intron 2 of 2	1
CFTR	ENST00000446805	c.-486T>G		5_prime_UTR_variant	Exon 2 of 6	4		ENSP00000417012.1
CFTR	ENST00000673785.1	c.-406+13452T>G		intron_variant	Intron 3 of 12			ENSP00000501235.1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 152058 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00623

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 86 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 70

Gnomad4 AFR exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00372 AC: 566 AN: 152176 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74384

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00476 Hom.: 0

Bravo AF: 0.00390

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:1 Benign:3

Feb 22, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 03, 2021

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Jun 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.-812T>G variant has been reported in the published literature in individuals affected with cystic fibrosis (CF) (PMIDs: 30296588 (2018), 23470247 (2013), 7540587 (1995)) and CFTR-related disorders (PMIDs: 25797027 (2015), 23470247 (2013), 18703788 (2008)). Functional studies yielded conflicting data on this variant's effect on CFTR promoter activity, transcription factor binding, and protein expression (PMIDs: 30296588 (2018), 25797027 (2015), 23470247 (2013), 7540587 (1995)). The frequency of this variant in the general population, 0.0052 (81/15406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. ClinVar contains an entry for this variant (URL: www.ncbi.nlm.nih.gov/clinvar, Variation ID: 51029). Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: BS1, BS2 -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.-812T>G variant (rs181008242, ClinVar Variation ID: 51029) is reported in the literature in individuals affected with CFTR-related disorders such as pancreatitis or congenital bilateral absence of the vas deferens (Giordano 2013, Mak 1999, Wilschanski 2006). This variant is found in the general population with an overall allele frequency of 0.34% (108/31356 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the upstream promoter region at a nucleotide that is weakly conserved, but in vitro functional assays are conflicting for the effects on transcription and transcription factor binding (Bergougnoux 2015, Giordano 2013, Kerschner 2019). While this variant is not associated with classic cystic fibrosis, the clinical significance for CFTR-related disorders is uncertain. References: Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015 Sep;14(5):646-53. PMID: 25797027. Giordano S et al. Molecular and functional analysis of the large 5' promoter region of CFTR gene revealed pathogenic mutations in CF and CFTR-related disorders. J Mol Diagn. 2013 May;15(3):331-40. PMID: 23470247. Kerschner JL et al. Screening for Regulatory Variants in 460 kb Encompassing the CFTR Locus in Cystic Fibrosis Patients. J Mol Diagn. 2019 Jan;21(1):70-80. PMID: 30296588. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. PMID: 10376575. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. PMID: 16840743. -

not specified Benign:1

Jan 18, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.7
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs181008242; hg19: chr7-117119337;