7-117614713-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting
The NM_000492.4(CFTR):c.3468G>T(p.Leu1156Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000379 in 1,602,446 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1156L) has been classified as Pathogenic.
Frequency
Consequence
NM_000492.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3468G>T | p.Leu1156Phe | missense_variant, splice_region_variant | Exon 21 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000178 AC: 27AN: 151970Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000132 AC: 33AN: 250770Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135530
GnomAD4 exome AF: 0.000401 AC: 581AN: 1450358Hom.: 7 Cov.: 27 AF XY: 0.000403 AC XY: 291AN XY: 722280
GnomAD4 genome AF: 0.000178 AC: 27AN: 152088Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10AN XY: 74352
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:3Benign:1
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The c.3468G>T variant (also known as p.L1156F), located in coding exon 21 of the CFTR gene, results from a G to T substitution at nucleotide position 3468. The amino acid change results in leucine to phenylalanine at codon 1156, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in multiple Japanese individuals with idiopathic, familial, hereditary, and alcoholic pancreatitis, including one individual with alcoholic pancreatitis who was homozygous for this alteration (Nakano E, Dig. Dis. Sci. 2015 May; 60(5):1297-307; Kondo S, Am. J. Physiol. Gastrointest. Liver Physiol. 2015 Aug; 309(4):G260-9). This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:3
The CFTR c.3468G>T; p.Leu1156Phe variant (rs139729994) has been described in several individuals affected with CFTR-related disorders but is also present in healthy controls (see link for SickKids CFTR database, Iso 2019, Kondo 2015, Li 2022, Nakano 2015). It is reported in ClinVar (Variation ID: 455775) and is observed in the East Asian population at an allele frequency of 0.16% (30/18,378 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.3468G>A; p.Leu1156Leu) has been described in individuals with a pancreatic sufficient form of cystic fibrosis who harbored another pathogenic variant on the opposite chromosome, in a homozygous individual with pancreatitis, and an individual with congenital bilateral absence of vas deferens (see link for SickKids CFTR database, Claustres 2017). The p.Leu1156Phe variant is in the last nucleotide of exon 21 and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. In vitro analyses of this variant demonstrate reduced protein expression and chloride transport activity when found with the Met470Val variant on the same chromosome, but no effect was seen in the presence of this variant alone (Kondo 2015). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Link to Cystic Fibrosis Mutation Database: http://www.genet.sickkids.on.ca/ Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. PMID: 28603918. Iso M et al. The CFTR gene variants in Japanese children with idiopathic pancreatitis. Hum Genome Var. 2019 Apr 11;6:17. PMID: 30992994. Li Q et al. Mutations in CFTR genes are associated with oligoasthenospermia in infertile men undergoing IVF. Andrologia. 2022 Apr;54(3):e14355. PMID: 34931337. Kondo S et al. Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G260-9. PMID: 26089335. Nakano E et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015 May;60(5):1297-307. PMID: 25492507. -
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PP3, PM2_moderate -
not specified Uncertain:1
Variant summary: CFTR c.3468G>T (p.Leu1156Phe) involves the alteration of a conserved nucleotide located in the last position of exon 21. 3/4 splice prediction tools predict a slight weakening of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. In the absence of splice change the variant would result in a non-conservative amino acid change that is located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251130 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0016 in the gnomAD database. This frequency is lower than estimated for a pathogenic variant in CFTR causing CFTR-related diseases (0.0016 vs. 0.013), allowing no conclusion about variant significance. The variant has been reported in two publications to be statistically associated with idiopathic and alcoholic chronic pancreatitis in Japanese patients (example, Kondo 2015, Nakano 2015, Iso_2019), however the sample size in these case-control studies was small and the authors did not adjust for the effect of other likely pathogenic or pathogenic CFTR, SPINK1, and CTRC variants that were found in co-occurrence in several patients in these cohorts. Another study reports this variant as a non-informative genotype (second allele or zygosity not specified) in at-least two Chinese individuals, one with CAVD and another with oligoasthenospermia (example, Li_2022). These report(s) do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. At least one publication reports experimental evidence evaluating an impact on protein function, showing that CFTR expression, Cl- current, HCO3- and Cl- transport was not different from wild-type in cells expressing the variant of interest, however, Cl-/HCO3- exchange activity was reduced to 30% of the wild-type levels and two patients had higher than normal sweat chloride levels (Kondo 2015). The variant of interest in combination with a benign polymorphism (V470M) had reduced CFTR expression (to 60-70%), CFTR-mediated HCO3-/Cl- transport (to 50-60%) and the Cl-/HCO3-exchange activity (to 2030%) compared to wild-type (Kondo 2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=1), VUS (n=4). Based on all these conflicting evidence outlined above, the variant was classified as a VUS, until more definitive functional and clinical studies become available. -
CFTR-related disorder Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at