rs587783132

Positions:

• chrX-154097665-T-A
• chrX-154097665-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4 PM2_Supporting PM6_Strong

This summary comes from the ClinGen Evidence Repository: The p.Met1Leu variant (NM_001110792.2) in MECP2 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID 16225173, GeneDx Internal Database)(PM6_strong, PP4). The p.Met1Leu variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Met1Leu variant in MECP2 is classified as a likely pathogenic variant based on the ACMG/AMP criteria (PM6_strong, PP4, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274666/MONDO:0010726/016

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 start_lost
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 1.87

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 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1A>T	p.Met1?	start_lost	1/3	ENST00000453960.7
MECP2	NM_004992.4	c.-160A>T		5_prime_UTR_variant	1/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1A>T	p.Met1?	start_lost	1/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.-160A>T		5_prime_UTR_variant	1/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 909411 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 282853

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

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	Dec 22, 2021	The p.Met1Leu variant (NM_001110792.2) in MECP2 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Rett syndrome (PMID 16225173, GeneDx Internal Database)(PM6_strong, PP4). The p.Met1Leu variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Met1Leu variant in MECP2 is classified as a likely pathogenic variant based on the ACMG/AMP criteria (PM6_strong, PP4, PM2_supporting). -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Nov 05, 2009	- -
Likely pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Feb 18, 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: This variant has been identified as a de novo occurrence in at least 2 individuals with Rett syndrome, without confirmation of paternity and maternity (PM6_Strong).PMID 16225173 , 19365833 ,ClinVar; [VCV000156661.6] At least one individual with this variant has been reported with a clinical phenotype consistent with Rett syndrome (PP4). PMID 19365833, PMID: 16225173. This variant is absent from gnomAD (PM2_Supporting). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2016	The c.1 A>T mutation in the MECP2 gene has been reported previously in association with classic Rett syndrome (Saunders et al., 2009). The mutation alters the initiator Methionine codon in the MeCP2_e1 transcript of the MECP2 gene, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. The variant is found in INFANT-EPI panel(s)." -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 11, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.065	.;T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.52	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.22	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.10	B;.
Vest4		0.84
MutPred		0.64		Loss of catalytic residue at M1 (P = 0.0138);Loss of catalytic residue at M1 (P = 0.0138);
MVP		0.97
ClinPred		0.80	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.32

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: rs587783132; hg19: chrX-153363122;