chrX-154030455-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001110792.2(MECP2):c.1409G>A(p.Arg470His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,209,420 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 88 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001110792.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MECP2 | NM_001110792.2 | c.1409G>A | p.Arg470His | missense_variant | Exon 3 of 3 | ENST00000453960.7 | NP_001104262.1 | |
MECP2 | NM_004992.4 | c.1373G>A | p.Arg458His | missense_variant | Exon 4 of 4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MECP2 | ENST00000453960.7 | c.1409G>A | p.Arg470His | missense_variant | Exon 3 of 3 | 1 | NM_001110792.2 | ENSP00000395535.2 | ||
MECP2 | ENST00000303391.11 | c.1373G>A | p.Arg458His | missense_variant | Exon 4 of 4 | 1 | NM_004992.4 | ENSP00000301948.6 | ||
MECP2 | ENST00000628176 | c.*745G>A | 3_prime_UTR_variant | Exon 5 of 5 | 3 | ENSP00000486978.1 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 19AN: 111191Hom.: 0 Cov.: 22 AF XY: 0.000240 AC XY: 8AN XY: 33373
GnomAD3 exomes AF: 0.000229 AC: 42AN: 183515Hom.: 0 AF XY: 0.000294 AC XY: 20AN XY: 67943
GnomAD4 exome AF: 0.000194 AC: 213AN: 1098179Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 80AN XY: 363533
GnomAD4 genome AF: 0.000162 AC: 18AN: 111241Hom.: 0 Cov.: 22 AF XY: 0.000239 AC XY: 8AN XY: 33433
ClinVar
Submissions by phenotype
not specified Benign:3
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not provided Benign:2
This variant is associated with the following publications: (PMID: 18810657, 28394482) -
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Rett syndrome Benign:1
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 2.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2, PMID 18810657, PMID: 18810657). Variant found in a case with an alternate molecular basis for disease (BP5_Supporting, PMID: 18810657). -
Severe neonatal-onset encephalopathy with microcephaly Benign:1
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Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Benign:1
MECP2 NM_004992.3 exon 4 p.Arg458His (c.1373G>A): This variant has been reported in the literature in 1 male individual with features of Rett syndrome, but did not meet diagnostic criteria (reported as p.Arg470His, Zhang 2017 PMID:28394482). This variant is present in 0.01% (10/52947) of European alleles, including 5 hemizygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/X-154030455-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:95193). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -
MECP2-related disorder Benign:1
This variant is classified as 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