rs61751445
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. BS2PP3BP5BS1
This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Thr311Met variant in MECP2 (NM_004992.3) is 0.022% and 0.01% in "Other" and South Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Thr311Met variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2) and found in 2 patients with an alternate molecular basis of disease (Baylor Genetics internal database, Invitae internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). As this variant meets 2 strong and 1 supporting benign criteria it can be classified as benign even though in silico predictions meet PP3. In summary, the p.Thr311Met variant in MECP2 is classified as benign for Rett syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170409/MONDO:0010726/036
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.968C>T | p.Thr323Met | missense_variant | 3/3 | ENST00000453960.7 | |
MECP2 | NM_004992.4 | c.932C>T | p.Thr311Met | missense_variant | 4/4 | ENST00000303391.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.968C>T | p.Thr323Met | missense_variant | 3/3 | 1 | NM_001110792.2 | ||
MECP2 | ENST00000303391.11 | c.932C>T | p.Thr311Met | missense_variant | 4/4 | 1 | NM_004992.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000356 AC: 4AN: 112460Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1AN XY: 34612
GnomAD3 exomes AF: 0.0000381 AC: 7AN: 183507Hom.: 0 AF XY: 0.0000294 AC XY: 2AN XY: 67941
GnomAD4 exome AF: 0.000116 AC: 127AN: 1098236Hom.: 0 Cov.: 35 AF XY: 0.000121 AC XY: 44AN XY: 363592
GnomAD4 genome ? AF: 0.0000356 AC: 4AN: 112512Hom.: 0 Cov.: 23 AF XY: 0.0000288 AC XY: 1AN XY: 34674
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2020 | This variant is associated with the following publications: (PMID: 22277191, 16672765, 28250423) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 16, 2018 | - - |
Rett syndrome Uncertain:1Benign:2
Benign, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Feb 19, 2022 | The allele frequency of the p.Thr311Met variant in MECP2 (NM_004992.3) is 0.022% and 0.01% in "Other" and South Asian sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Thr311Met variant is observed in at least 2 unaffected individuals (GeneDx internal database) (BS2) and found in 2 patients with an alternate molecular basis of disease (Baylor Genetics internal database, Invitae internal database) (BP5). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). As this variant meets 2 strong and 1 supporting benign criteria it can be classified as benign even though in silico predictions meet PP3. In summary, the p.Thr311Met variant in MECP2 is classified as benign for Rett syndrome based on the ACMG/AMP criteria (BS1, BS2, BP5). - |
Uncertain significance, no assertion criteria provided | curation | RettBASE | Sep 27, 2012 | - - |
Likely benign, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jan 09, 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 benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is between 0.008% and 0.03% (BS1). Variant is found in an individual with an alternate molecular basis of disease (BP5). (ClinVar Variation ID:36496) The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2018 | Variant summary: MECP2 c.932C>T (p.Thr311Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 178987 control chromosomes including 2 hemizygotes (gnomAD). The observed variant frequency is approximately 4.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MECP2 causing Rett Syndrome phenotype (8.3e-06), strongly suggesting that the variant is benign. The variant, c.932C>T, has been reported in the literature in one individual affected with Rett Syndrome (Kim_2006). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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. Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | curation | RettBASE | Sep 27, 2012 | - - |
Severe neonatal-onset encephalopathy with microcephaly Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
MECP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 03, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at