7-117531079-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000492.4(CFTR):c.454A>T(p.Met152Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.454A>T | p.Met152Leu | missense_variant | Exon 4 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250304Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135224
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461332Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 726920
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74472
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2
The p.M152L variant (also known as c.454A>T), located in coding exon 4 of the CFTR gene, results from an A to T substitution at nucleotide position 454. The methionine at codon 152 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in an individual referred for evaluation for cystic fibrosis in conjunction with a 5T allele; however, specific clinical information and phase of the variants was not provided (El-Seedy A et al. Cell. Mol. Biol. (Noisy-le-grand), 2016 Nov;62:21-28). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 152 of the CFTR protein (p.Met152Leu). This variant is present in population databases (rs397508721, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 28040058). ClinVar contains an entry for this variant (Variation ID: 439479). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Variant summary: CFTR c.454A>T (p.Met152Leu) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250304 control chromosomes. c.454A>T has been reported in the literature in at least one individual affected with CFTR or CFTR-Related Disease, however without strong evidence for causality (e.g., El-Seedy_2016, Saferali_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. The most pronounced variant effect resulted in approximately (Gt channel conductance) 31% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 28040058, 34996830). ClinVar contains an entry for this variant (Variation ID: 439479). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
CFTR-related disorder Uncertain:1
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not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at