X-154097603-C-T

Position:

• chrX-154097603-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM6 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.62+1G>A (NM_001110792.2) variant in MECP2 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.62+1G>A variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 15737703) (PM6, PP4). The c.62+1G>A variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the c.62+1G>A variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6, PP4, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274678/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 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 1.69

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 Pathogenic. Variant got 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.62+1G>A		splice_donor_variant		ENST00000453960.7
MECP2	NM_004992.4	c.-99+1G>A		splice_donor_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.-99+1G>A		splice_donor_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.62+1G>A		splice_donor_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 940429 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 293419

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: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	curation	RettBASE	Feb 18, 2008	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Aug 14, 2023	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 pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). This variant has been identified as a de novo occurrence in an individual with Rett syndrome without confirmation of paternity and maternity (PM6, PMID: 15737703). At least one patient with this variant has been reported in an individual with a clinical phenotype suggestive of Rett syndrome (PP4, PMID: 15737703). This variant is absent from gnomAD (PM2_Supporting). -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Dec 22, 2021	The c.62+1G>A (NM_001110792.2) variant in MECP2 is predicted to affect a canonical splice site and lead to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The c.62+1G>A variant in MECP2 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with Rett syndrome (PMID 15737703) (PM6, PP4). The c.62+1G>A variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the c.62+1G>A variant in MECP2 is classified as pathogenic for Rett syndrome based on the ACMG/AMP criteria (PVS1, PM6, PP4, PM2_supporting). -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2017

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MECP2 are known to be pathogenic (PMID: 12180070). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to be de novo in an individual affected with Rett syndrome (PMID: 15737703). It is also known as "Ex1 donor site" in the literature. ClinVar contains an entry for this variant (Variation ID: 189776). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 1 of the MECP2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The MECP2 gene has multiple clinically relevant isoforms. The c.62+1G>A variant occurs in alternate transcript NM_001110792.1, which corresponds to position c.-99+1G>A in NM_004992.3, the primary transcript listed in the Methods. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	34
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	D;D;D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 17
DS_DL_spliceai		0.95		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205048; hg19: chrX-153363060;