NM_000492.4:c.1210-11T>G

Variant names:

• chr7-117548630-T-G
• rs73715573
• NM_000492.4:c.1210-11T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS1_Supporting

The NM_000492.4(CFTR):​c.1210-11T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00979 in 1,536,052 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,other (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (27 hom.)
• Consequence: CFTR NM_000492.4 intron
• Scores: Splicing: ADA: 0.9867
• Clinical Significance: Pathogenic/Likely pathogenic; other criteria provided, multiple submitters, no conflicts P:18 U:1 O:1
• Conservation: PhyloP100: 0.236

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:40144): (CFTR antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP5: Variant 7-117548630-T-G is Pathogenic according to our data. Variant chr7-117548630-T-G is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 178713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117548630-T-G is described in Lovd as [Likely_pathogenic]. Variant chr7-117548630-T-G is described in Lovd as [Likely_benign].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00941 (1340/142364) while in subpopulation EAS AF= 0.0252 (117/4640). AF 95% confidence interval is 0.0215. There are 10 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-11T>G		intron_variant	Intron 9 of 26	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6091A>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-11T>G		intron_variant	Intron 9 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00942 AC: 1340 AN: 142252 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.00131

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0123

GnomAD3 exomes AF: 0.00861 AC: 2046 AN: 237638 Hom.: 0 AF XY: 0.00857 AC XY: 1107 AN XY: 129228

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00831

Gnomad ASJ exome AF: 0.0336

Gnomad EAS exome AF: 0.0202

Gnomad SAS exome AF: 0.00859

Gnomad FIN exome AF: 0.000763

Gnomad NFE exome AF: 0.00712

Gnomad OTH exome AF: 0.00712

GnomAD4 exome AF: 0.00983 AC: 13696 AN: 1393688 Hom.: 27 Cov.: 37 AF XY: 0.00984 AC XY: 6824 AN XY: 693280

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.00895

Gnomad4 ASJ exome AF: 0.0381

Gnomad4 EAS exome AF: 0.0143

Gnomad4 SAS exome AF: 0.00990

Gnomad4 FIN exome AF: 0.00128

Gnomad4 NFE exome AF: 0.00933

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.00941 AC: 1340 AN: 142364 Hom.: 10 Cov.: 32 AF XY: 0.00942 AC XY: 654 AN XY: 69436

Gnomad4 AFR AF: 0.00319

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.0481

Gnomad4 EAS AF: 0.0252

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.00131

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0122

Alfa AF: 0.0132 Hom.: 1

ClinVar

Significance: Pathogenic/Likely pathogenic; other

Submissions summary: Pathogenic:18 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:9 Uncertain:1

Sep 25, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3 -

-

Suma Genomics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c. c.1210-11T>G occurs in the poly T tract between the branch site and the acceptor site in intron 9 (legacy intron 8) of CFTR. This combined poly-T and TG tract genotype is also designated as TG12-5T. Variants that disrupt this tract (commonly referred to as "5T" variants, also called "c.1210-12T[5]" or "c.1210-7_1210-6del") have frequently been associated with CFTR-related diseases when found in compound heterozygosity with other pathogenic mutations in CFTR. CFTR c.1210-11T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, at least one functional study shows a moderate impact to proper CFTR mRNA expression by altering the splicing efficiency of exon 9 in vitro (Hefferon_2004). The variant allele was found at a frequency of 0.0086 in 237638 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-related diseases allowing no conclusion about variant significance. Similar 5T variants have been reported in the literature in numerous individuals affected with CF, CBAVD, and other CFTR-related diseases, but have also been found in unaffected controls when in compound heterozygosity with other pathogenic mutants in CFTR. (examples- Cuppens_1998, Noone_2001, Groman_2004, Sun_2006, Ratbi_2007, Tomaiudo_2010, Ballard_2015). The penetrance of 5T variants is influenced by the presence of other CFTR variants (e.g. p.R117H) and the length of the adjacent TG tract on the same allele (in cis). In most 5T CFTR genes, the number of TG repeats found in cis determines whether the amount of functional CFTR proteins that will be translated does fall above or below the critical level for normal CFTR function (Castellani_2008). Approximately 90% of the 5T CFTR genes found in CBAVD patients associate with TG12 or TG13, while about 10% associate with TG11 (Castellani_2008). In compound heterozygosity with a CF-causing mutation, or in homozygosity, R117H-5T generally results in pancreatic sufficient CF. A TG12-5T or TG13-5T CFTR gene found in compound heterozygosity with a CF-causing mutation, or possibly even in homozygosity, will in general result in a CFTR-related disorder, such as Congenital Bilateral Absence of the Vas Deferens (CBAVD) or chronic idiopathic pancreatitis. Some CBAVD patients may develop mild lung symptoms. In exceptional cases, TG12-5T and TG13-5T, may cause a mild form of CF. Three of five other ClinVar submitters (evaluation after 2014) have cited 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. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 09, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change, also referred to as 5T;TG12 or TG12-5T in the literature, consists of 12 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[12]T[5] allele has been observed in males with congenital bilateral absence of the vas deferens (CBAVD) and in both males and females with cystic fibrosis (CF) when present on the opposite chromosome (in trans) from a severe pathogenic CFTR variant (PMID: 14685937). When this allele is observed in trans with a severe pathogenic CFTR variant, the penetrance of CFTR-related conditions (CBAVD and/or non-classic CF) is expected to be high (>90%); however, the penetrance of classic CF is low (<20%) (PMID: 14685937, 27447098). Individuals who are homozygous for this variant, or who have this variant in combination with TG[11]T[5], are likely to be asymptomatic (PMID: 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). 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). For these reasons, this variant has been classified as Pathogenic. -

May 24, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4 Other:1

May 19, 2016

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 12TG-5T variant in IVS8 is a mild pathogenic 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/ -

Mar 23, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 22427236, 18507830, 9435322, 23092102, 23554779, 28152038, 28801929, 14685937, 22430190, 7739684, 25033378, 23951356, 7573058, 7506096, 7684646, 1381723, 18306312, 14993601, 12068373, 17394391, 27488005, 28174639, 16778595, 27996019, 25383785, 26500004, 29216686, 26989879, 20560922, 29997923, 28546993, 23416327, 26253411, 17314234, 18616886, 27447098, 22842702, 20977904, 19812525, 15070876, 31180159, 34426522, 34782259) -

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

Sep 02, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

-

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org) dataset at total allele frequency of 0.849%. Intron variant. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10556281, 14685937, 9435322). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21658649, 25383785, 27469177). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000178713 / PMID: 28152038). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3+PS4+PM3 -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Sep 13, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

May 01, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1210-34TG[12]T[5] in intron 9 of CFTR is a variant of the polymorphic TG[n ]T[m] region adjacent to exon 10. The TG[12]T[5] allele has been identified in 5 .9% (17/290) of Ashkenazi Jewish chromosomes, 3% (47/1472) of East Asian chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g/), and is known to affect mRNA splicing (Chu 1993). Studies have shown that lo nger TG repeat sizes (TG11, 12 and 13) in individuals with T[5] have a greater s usceptibility to disease than those with smaller TG repeat sizes when present in trans with a pathogenic CFTR variant (Chu 1992, Cuppens 1998, Groman 2004, Radp our 2007). The associated CF-related symptoms are congenital bilateral absence o f the vas deferens (CBAVD), male infertility, mild to classic forms of cystic fi brosis, with severity depending of the CF variant on the opposite allele (Chillo n 1995). In summary, the 1210-34TG[12]T[5] variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. AC MG/AMP Criteria applied: PM3_Strong, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.8
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.080		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: rs73715573; hg19: chr7-117188684; COSMIC: COSV99135863;