chr7-117534333-C-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting
The NM_000492.4(CFTR):c.547C>A(p.Leu183Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,602,238 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L183H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.547C>A | p.Leu183Ile | missense_variant | 5/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.547C>A | p.Leu183Ile | missense_variant | 5/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000299 AC: 75AN: 250676Hom.: 0 AF XY: 0.000369 AC XY: 50AN XY: 135546
GnomAD4 exome AF: 0.000177 AC: 256AN: 1449966Hom.: 2 Cov.: 26 AF XY: 0.000260 AC XY: 188AN XY: 722146
GnomAD4 genome AF: 0.000105 AC: 16AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74458
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:3Benign:1Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2023 | The p.L183I variant (also known as c.547C>A), located in coding exon 5 of the CFTR gene, results from a C to A substitution at nucleotide position 547. The leucine at codon 183 is replaced by isoleucine, an amino acid with highly similar properties. This variant was identified in an individual with lower respiratory tract infections, sinusitis, failure to thrive and elevated sweat chloride levels of 57 and 60; a second CFTR alteration was not identified (Shastri SS et al. J. Cyst. Fibros., 2008 Mar;7:110-5). It was also identified in a 28-year-old male with normal sweat chloride levels, bronchiectasis, and pulmonary non-tuberculosis mycobacterial infection; a second CFTR alteration was not identified (Ziedalski TM et al. Chest, 2006 Oct;130:995-1002). An in vitro study attempting to identify exonic alterations which weaken core splicing motifs using hybrid minigene constructs revealed a increased basal exon skipping of exon 5 with this particular nucleotide substitution compared to the wild type construct (Aissat A et al. Hum. Mutat., 2013 Jun;34:873-81). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The missense variant c.547C>A(p.Leu183Ile) in the CFTR gene has been reported previously in a heterozygous state in individuals affected with asthma and chronic pancreatitis. An in vitro study attempting to identify exonic alterations which weaken core splicing motifs using hybrid minigene constructs revealed an increased basal exon skipping of exon 5 with this particular nucleotide substitution compared to the wild-type construct (Muthuswamy et al., 2014; Aissat et al., 2013). This variant is reported with the allele frequency (0.02%) in the gnomAD Exomes and novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/ Likely Benign. The amino acid Leucine at position 183 is changed to a Isoleucine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Leu183Ile in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Based on available evidence to date, the clinical significance of this alteration remains unclear. For these reasons, this variant has been classified as Uncertain Significance. - |
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 30, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2020 | Variant summary: CFTR c.547C>A (p.Leu183Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 250676 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0003 vs 0.013), allowing no conclusion about variant significance. c.547C>A has been reported in the literature in individuals affected with Cystic Fibrosis or CFTR related disorders (Ziedalski_2006, Shastri_2008). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, although one study showed this variant did not lead to exon skipping (Aissat_2013). One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at