rs121908789

Positions:

• chr7-117642487-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3773dupT​(p.Leu1258fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: -0.238

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117642487-C-CT is Pathogenic according to our data. Variant chr7-117642487-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 38726.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3773dupT	p.Leu1258fs	frameshift_variant	23/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3773dupT	p.Leu1258fs	frameshift_variant	23/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251050 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461394 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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: 0.00

Alfa AF: 0.0000263 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 3 unrelated patients 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: PVS1_STR, PS3_MOD, PM2_SUP, PM3_STR, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000492.3(CFTR):c.3773dupT(L1258Ffs*7, aka 3905insT) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 19724303 and 23974870. Classification of NM_000492.3(CFTR):c.3773dupT(L1258Ffs*7, aka 3905insT) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 11, 2020	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2023	The c.3773dupT pathogenic mutation (also known as c.3773_3774insT and 3905insT), located in coding exon 23 of the CFTR gene, results from a duplication of T at nucleotide position 3773, causing a translational frameshift with a predicted alternate stop codon (p.L1258Ffs*7). This mutation was described in 30 compound heterozygous individuals with cystic fibrosis characterized by elevated sweat chloride levels, failure to thrive, pancreatic insufficiency, and progressively decreasing lung function (Schibler A et al. Eur. Respir. J., 2001 Jun;17:1181-6). Immunocytochemical studies demonstrated that this alteration significantly reduces the amount of mature CFTR protein found in the apical membranes of nasal epithelia (Sanz J et al. Eur. J. Hum. Genet., 2010 Feb;18:212-7). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Leu1258Phefs*7) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs796566397, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 19724303, 21520337, 23974870). This variant is also known as 3905insT. ClinVar contains an entry for this variant (Variation ID: 38726). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 01, 2021	The frameshift variant causes the premature termination of CFTR protein synthesis. This variant causes cystic fibrosis (CF) when co-occurring with a CF-causing variant in trans and has also been reported in individuals affected with chronic pancreatitis in the published literature (PMID: 7525450 (1994), 23974870 (2013), 21520337 (2011), 19724303 (2010)). Additionally, immunohistochemical staining of the CFTR protein in patient nasal epithelial cells revealed that this variant significantly impairs expression (PMID: 19724303 (2010)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CFTR: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	The CFTR c.3773dupT; p.Leu1258PhefsTer7 (rs387906370) variant, also known as 3905insT, is reported in multiple individuals diagnosed with cystic fibrosis (Dork 1994, Gallati 2009, Hirtz 2004, Sosnay 2013) and is generally associated with pancreatic insufficiency (Ooi 2012, Sosnay 2013, CFTR2 database). Functional characterization of the variant indicates that the transcript is insensitive to nonsense-medicated decay or nonsense-associated alternative splicing (Sanz 2010). The variant protein fails to mature and localize to the cell surface (Sanz 2010), resulting in severe reduction in chloride transport activity (Hirtz 2004). This variant is also reported in the ClinVar database (Variation ID: 38726). It is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant introduces a frameshift, and functional studies indicate it results in a truncated, inactive protein. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994; 94(5):533-42. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Hirtz S et al. CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis. Gastroenterology. 2004; 2004 Oct;127(4):1085-95. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sanz J et al. The CFTR frameshift mutation 3905insT and its effect at transcript and protein level. Eur J Hum Genet. 2010; 18(2):212-7. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 20, 2021	- -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 22, 2024	The CFTR c.3773dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu1258Phefs*7). This variant, sometimes described as 3905insT using legacy nomenclature, has been reported in the compound heterozygous or homozygous state in many individuals with cystic fibrosis (Liechti-Gallati et al. 1992. PubMed ID: 1380689; Hirtz S et al 2004. PubMed ID: 15480987; Hergersberg M et al 1997. PubMed ID: 9254853; Sanz J et al 2009. PubMed ID: 19724303; CFTR2.org), as well as CFTR-related disorders including pancreatic insufficiency (Ooi and Durie. 2012. PubMed ID: 22658665) and congenital bilateral absence of the vas deferens (Steiner et al. 2011. PubMed ID: 21520337). This variant was also reported to be the second most common pathogenic CFTR variant in the Swiss population and is associated with a severe phenotype when in the presence of p.Phe508del (Hergersberg M et al 1997. PubMed ID: 9254853). Functional studies indicate this variant does not result in nonsense-mediated decay or nonsense-associated alternative splicing, but does reduce the amount of CFTR protein at the apical membrane (Sanz J et al 2009. PubMed ID: 19724303). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908789; hg19: chr7-117282541;