7-117548628-GTTTTTT-GTTTT

Position:

• chr7-117548628-GTTTTTT-GTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000492.4(CFTR):​c.1210-7_1210-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,547,804 control chromosomes in the GnomAD database, including 354 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.036 (122 hom., cov: 31)
  • Exomes 𝑓: 0.029 (232 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:3 B:1 O:4
• Conservation: PhyloP100: 0.565

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-7_1210-6delTT		splice_region_variant, intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6091_222-6090delAA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-7_1210-6delTT		splice_region_variant, intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5089 AN: 142494 Hom.: 122 Cov.: 31

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.0449

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00812

Gnomad FIN AF: 0.0328

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0303

GnomAD3 exomes AF: 0.0223 AC: 4575 AN: 205052 Hom.: 13 AF XY: 0.0219 AC XY: 2449 AN XY: 111880

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.00636

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0286 AC: 40213 AN: 1405206 Hom.: 232 AF XY: 0.0278 AC XY: 19403 AN XY: 699172

Gnomad4 AFR exome AF: 0.0558

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.000419

Gnomad4 SAS exome AF: 0.00648

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0316

Gnomad4 OTH exome AF: 0.0300

GnomAD4 genome AF: 0.0357 AC: 5090 AN: 142598 Hom.: 122 Cov.: 31 AF XY: 0.0351 AC XY: 2439 AN XY: 69528

Gnomad4 AFR AF: 0.0620

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00857

Gnomad4 FIN AF: 0.0328

Gnomad4 NFE AF: 0.0311

Gnomad4 OTH AF: 0.0300

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16 Uncertain:3 Benign:1 Other:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:2 Benign:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000492.3(CFTR):c.1210-7_1210-6delTT(aka IVS8-5T or 5T) is a variant within the polyT tract located within intron 8 of the CFTR gene. 5T has been observed in individuals diagnosed with cystic fibrosis but has also been observed in healthy individuals (PMID 23974870; gnomAD: AFR 7.085%). Please note that 5T is not associated with cystic fibrosis when detected in isolation and the American College of Medical Genetics does not recommend reporting 5T status through routine carrier screening when detected in isolation. However, 5T is considered an incompletely penetrant pathogenic variant that may result in cystic fibrosis when present on the same chromosome as R117H and combined with another pathogenic CFTR variant on the other chromosome. In the absence of R117H, 5T may be associated with CFTR-related disorders depending on the presence of other deleterious variants in the gene. In summary, classification of 5T is based on the following criteria: high frequency variant with incomplete penetrance and variable severity dependent on the presence of other variants in the CFTR gene. Please note: this allele was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	The severity of lung disease in individuals heterozygous or homozygous for p.Arg117His depends on the presence of a variation in the poly T tract of intron 9, c.1210-12T[5_9] [Massie et al 2001]. Individuals with a CF-causing variant plus the 5T variant in cis with p.Arg117His usually develop the lung disease of CF, but those individuals with p.Arg117His and the 7T variant or the 9T variant have a highly variable phenotype that can range from no symptoms to mild lung disease [Kiesewetter et al 1993, Chmiel et al 1999]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2021	This sequence change, also referred to as 5T;TG11 or TG11-5T in the literature, consists of 11 TG and 5 T sequence repeats on the same chromosome, and is located in intron 9 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. The TG[11]T[5] allele has been observed in males with congenital bilateral absence of the vas deferens (CBAVD), with a penetrance of ~32%, when present on the opposite chromosome (in trans) from a severe pathogenic CFTR variant (PMID: 14685937). The TG[11]T[5] allele is not expected to cause cystic fibrosis in either males or females when in trans with a severe pathogenic CFTR variant (PMID: 14685937, 27447098), although individuals with borderline sweat chloride results and/or mild respiratory disease have been reported (PMID: 16778595). The combination of the TG[11]T[5] allele in trans with another 5T allele (TG11-13), is unlikely to be associated with CFTR-related symptoms (PMID: 21520337, 34196078). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies demonstrate that the 5T allele leads to exclusion of exon 10 (referred to as exon 9 in some publications) from the mRNA, which ultimately results in a non-functional CFTR protein (PMID: 7691356, 7684641, 10556281, 14685937, 21658649) and partial loss of function. Importantly, the number of TG repeats (11, 12 or 13) modifies the extent of exon 10 skipping when in cis with the 5T allele (PMID: 14685937, 10556281, 9435322). In a mini-gene assay, the percentage of CFTR mRNA without exon 10 was 54% for TG[11]T[5], 72% for TG[12]T[5] and 100% for TG[13]T[5] (PMID: 10556281). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the CFTR gene, it has been classified as Pathogenic (low penetrance). -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	The 11TG-5T variant in IVS8 is the mildest type of 5T variant. When combined with a pathogenic variant on the other chromosome, this variant is not expected to cause classic cystic fibrosis (CF), but may cause a CFTR-related disorder (i.e., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease) (CFTR2 database). Link to CFTR2 database: http://cftr2.org/ -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2017	The c.1210-7_1210-6delTT variant in the CFTR gene, also reported as c.1210-12T[5] and commonly referred to as the 5T allele, occurs in the poly T tract in intron 9 (intron 8 using legacy exon numbering). The c.1210-7_1210-6delTT variant acts as a disease susceptibility variant with variable penetrance (CFTR2 Mutation Database; Ong et al., 2017). Specifically, the c.1210-7_1210-6delTT variant has been associated with recessive CFTR-related disorders when seen in trans with another severe pathogenic variant in the CFTR gene. Disease features described include elevated sweat chloride levels, congenital bilateral absence of the vas deferens (CBAVD) in males, and non-classic to classic cystic fibrosis (Chillon et al., 1995; Ong et al., 2017). However, the penetrance of the c.1210-7_1210-6delTT variant is influenced by the presence of other variants (e.g. R117H) and the length of the adjacent TG tract on the same allele (in cis). Longer TG repeat sizes (TG12 and TG13) in cis with c.1210-7_1210-6delTT are associated with a greater susceptibility to disease than c.1210-7_1210-6delTT in cis with a smaller TG repeat size (TG11) (Cuppens et al., 1998; Groman et al., 2004; Ong et al., 2017). RNA studies demonstrate that the c.1210-7_1210-6delTT variant results in abnormal splicing of exon 10 in a significant percentage of transcripts (Chu et al., 1993; Hefferon et al., 2002). The c.1210-7_1210-6delTT variant has been observed in at least 5% of alleles from of individuals of European background (Chillon et al., 1995). Therefore, based on the information available, we interpret c.1210-7_1210-6delTT as a pathogenic susceptibility variant with variable penetrance. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 28, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2019	Variant summary: CFTR c.1210-12[5] (also known as c.5T_TG11 or c.1210-7_1210-6delTT) occurs in the poly T tract in intron 9. 5/5 computational tools predict no significant impact on normal splicing. However, at least one functional study shows a moderate impact to proper CFTR mRNA expression in vitro (Hefferon_2004). The variant has been reported in the literature in numerous individuals affected with Congenital Bilateral Absence of the Vas Deferens, as well as some individuals who are asymptomatic. The variant is associated with CFTR-related disorders when in trans with another severe pathogenic CFTR variant. The penetrance of the c.1210-12[5] variant is influenced by the presence of other variants (e.g. R117H) and the length of the adjacent TG tract on the same allele (in cis). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, four of which classified the variant as pathogenic. In addition, ACMG guidelines for reporting CFTR mutations consider the 5T allele as associated as a trans mutation in CBAVD (ACMG guideline_2011). Based on the evidence outlined above, the variant was classified as pathogenic for CBAVD and CFTR-related disorders. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not specified Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 14, 2016	The c.1210-34TG[11]T[5] in intron 9 of CFTR is a variant of the polymorphic TG[n ]T[m] region adjacent to exon 10. The T[5] allele has been identified in an ave rage of 4.3% of individuals from a population of European American chromosomes ( Groman 2004) and has been shown to affect splicing in small percentage of transc ripts (Chu 1993). The length of the TG tract modifies the overall risk with lon ger TG repeat sizes (TG 12 and 13) showing the greatest susceptibility to diseas e when present in trans with a pathogenic cystic fibrosis variant (Chu 1992, Cup pens 1998, Groman 2004, Radpour 2007). The combination of the T[5] and TG[11] is least likely to exhibit an abnormal phenotype but a modest increased risk canno t be excluded (Cuppens 1998; Groman 2004). The associated CF-related symptoms ar e congenital bilateral absence of the vas deferens (CBAVD), male infertility, mi ld to classic forms of cystic fibrosis, with severity depending of the CF varian t on the opposite allele (Chillon 1995). In summary, the clinical significance o f the 1210-34TG[11]T[5] is uncertain. -
Pathogenic, flagged submission	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 08, 2020	- -

Obstructive azoospermia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Reproductive Genetics, University of Münster

Aug 23, 2021

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2019

The 5T variant, located in intron 9 of the CFTR gene, is an alteration within the poly-thymidine tract, which decreases the efficiency of exon 10 splicing. The 5T variant in trans with a pathogenic CFTR mutation, or in the homozygous state, has been associated with CFTR-related disorders, including bronchiectasis (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98), acute recurrent or chronic pancreatitis (Werlin S et al. J. Pediatr. Gastroenterol. Nutr., 2015 May;60:675-9; Masson E et al. PLoS ONE, 2013 Aug;8:e73522), and congenital bilateral absence of the vas deferens (CBAVD) (Bombieri C et al. J. Cyst. Fibros., 2011 Jun;10 Suppl 2:S86-102). The effect of 5T on exon 10 splicing is influenced by the adjacent TG tract, which usually consists of 11, 12, or 13 TG repeats. Increasing TG tract length correlates with decreased amount of full-length CFTR, thereby leading to higher likelihood of a cystic fibrosis phenotype (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98); information regarding the number of TG repeats adjacent to the 5T allele is limited in pancreatitis and bronchiectasis research (Mantovani V et al. Clin. Chem., 2007 Mar;53:531-3; Bombieri C et al. J. Cyst. Fibros., 2011 Jun;10 Suppl 2:S86-102). -

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 01, 2022

ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Congenital bilateral absence of vas deferens Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 07-07-2016 by Lab LabCorp. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Bronchiectasis with or without elevated sweat chloride 1, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 28, 2008

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant classified as Pathogenic and reported on 07-26-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1805177; hg19: chr7-117188682;