7-117480087-G-C

Variant names:

• chr7-117480087-G-C
• rs1800501
• NM_000492.4:c.-8G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.-8G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,613,616 control chromosomes in the GnomAD database, including 2,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (175 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2282 hom.)
• Consequence: CFTR NM_000492.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.212
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-117480087-G-C is Benign according to our data. Variant chr7-117480087-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.-8G>C		5_prime_UTR	Exon 1 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.-8G>C		5_prime_UTR	Exon 1 of 27	ENSP00000003084.6
	CFTR	ENST00000546407.1	TSL:1	n.166+4279G>C		intron	N/A
	CFTR	ENST00000647639.1		n.77G>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6527 AN: 152004 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.00971

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.0154

Gnomad FIN AF: 0.0975

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0601

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0457 AC: 11486 AN: 251068 AF XY: 0.0455

Gnomad AFR exome AF: 0.00802

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0958

Gnomad NFE exome AF: 0.0565

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0528 AC: 77166 AN: 1461494 Hom.: 2282 Cov.: 31 AF XY: 0.0519 AC XY: 37759 AN XY: 727074

African (AFR) AF: 0.00726 AC: 243 AN: 33474

American (AMR) AF: 0.0198 AC: 885 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 845 AN: 26134

East Asian (EAS) AF: 0.0583 AC: 2315 AN: 39698

South Asian (SAS) AF: 0.0145 AC: 1252 AN: 86250

European-Finnish (FIN) AF: 0.0903 AC: 4817 AN: 53362

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5762

European-Non Finnish (NFE) AF: 0.0575 AC: 63947 AN: 1111724

Other (OTH) AF: 0.0465 AC: 2810 AN: 60372

GnomAD4 genome AF: 0.0429 AC: 6529 AN: 152122 Hom.: 175 Cov.: 32 AF XY: 0.0443 AC XY: 3293 AN XY: 74348

African (AFR) AF: 0.00968 AC: 402 AN: 41508

American (AMR) AF: 0.0252 AC: 385 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3470

East Asian (EAS) AF: 0.0607 AC: 313 AN: 5160

South Asian (SAS) AF: 0.0154 AC: 74 AN: 4808

European-Finnish (FIN) AF: 0.0975 AC: 1033 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0601 AC: 4085 AN: 67988

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0540 Hom.: 93

Bravo AF: 0.0368

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0514

EpiControl AF: 0.0444

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 06, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

-8G>C in exon 1 of CFTR: This variant is not expected to have clinical significa nce because it has been identified in 5.5% (477/8600) of European American chrom osomes from a broad population by the NHLBI Exome Sequencing Project (http://evs .gs.washington.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cystic fibrosis Benign:5

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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: BS1, BS2, BS3

Aug 13, 2024

Johns Hopkins Genomics, Johns Hopkins University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither

Nov 19, 2014

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.

not provided Benign:3

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30296588, 19652440, 27022295, 15905293)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

CFTR-related disorder Benign:2

May 10, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Hereditary pancreatitis Benign:1

Jan 30, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		0.21
PromoterAI		-0.032	Neutral
Mutation Taster		=276/24	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800501; hg19: chr7-117120141; COSMIC: COSV50080503; COSMIC: COSV50080503;