rs61748410
Variant summary
Our verdict is Likely pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM2_SupportingPM5PM1PS4_ModeratePS3_SupportingPM6
This summary comes from the ClinGen Evidence Repository: The p.Phe157Ile variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with a clinical phenotype suggestive of MECP2-related conditions (PMID 16832102) (PM6). The p.Phe157Ile variant in MECP2 has been observed in 2 additional individuals with Rett syndrome (RettBASE) (PS4_moderate). The p.Phe157Ile variant occurs in the well-characterized methyl-DNA binding functional domain of MECP2 (PM1). A pathogenic missense variant (p.Phe157Leu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 19722030, 16225173, 22476991, 30536762, 15675358, ClinVar) (PM5). The p.Phe157Ile variant in MECP2 is absent from gnomAD (PM2_supporting). A MECP2 chromatin binding assay has shown that this variant impacts protein function (PMID 27929079) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Phe157Ile variant in MECP2 is classified as Likely Pathogenic for MECP2-related conditions based on the ACMG/AMP criteria (PM1, PM5, PM6, PS4_moderate, PM2_supporting, PS3_supporting, PP3 ). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274628/MONDO:0010726/016
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.505T>A | p.Phe169Ile | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.469T>A | p.Phe157Ile | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.505T>A | p.Phe169Ile | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.469T>A | p.Phe157Ile | missense_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Rett syndrome Pathogenic:2Uncertain:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Oct 11, 2022 | The p.Phe157Ile variant in MECP2 (NM_004992.3) occurs in the de novo state (biological parentage unconfirmed) in an individual with a clinical phenotype suggestive of MECP2-related conditions (PMID 16832102) (PM6). The p.Phe157Ile variant in MECP2 has been observed in 2 additional individuals with Rett syndrome (RettBASE) (PS4_moderate). The p.Phe157Ile variant occurs in the well-characterized methyl-DNA binding functional domain of MECP2 (PM1). A pathogenic missense variant (p.Phe157Leu) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 19722030, 16225173, 22476991, 30536762, 15675358, ClinVar) (PM5). The p.Phe157Ile variant in MECP2 is absent from gnomAD (PM2_supporting). A MECP2 chromatin binding assay has shown that this variant impacts protein function (PMID 27929079) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Phe157Ile variant in MECP2 is classified as Likely Pathogenic for MECP2-related conditions based on the ACMG/AMP criteria (PM1, PM5, PM6, PS4_moderate, PM2_supporting, PS3_supporting, PP3 ). - |
Likely pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jan 10, 2024 | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as likely pathogenic. At least the following criteria are met: Occurs in the well-characterized Methyl-DNA binding (MDB) functional domain of MECP2 (PM1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6). PMID 16832102 Has been observed in at least 3 individuals with phenotypes consistent with MECP2-related disease(PS4_Moderate). PMID 16832102, ClinVar Variation ID:143585 This variant is absent from gnomAD (PM2_Supporting). Well-established in vitro or in vivo functional studies supportive of a damaging effect on the protein function (PS3_supporting). PMID 27929079 - |
Uncertain significance, no assertion criteria provided | curation | RettBASE | Nov 01, 2007 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Severe neonatal-onset encephalopathy with microcephaly Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Nov 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at