X-154031359-A-T

Position:

• chrX-154031359-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3 PM2_Supporting PM5 PM1 PS4_Moderate PS3_Supporting PM6

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: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 8.82

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:2 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.6	D;D;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;.;.;.
Sift4G	Benign	0.29	T;T;.;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.80
MutPred		0.97		Loss of methylation at R162 (P = 0.1113);.;Loss of methylation at R162 (P = 0.1113);.;.;
MVP		1.0
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61748410; hg19: chrX-153296810;