X-154030381-C-A

Position:

• chrX-154030381-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Glu483Ter variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1_Moderate). The p.Glu483Ter variant in MECP2 is absent from gnomAD (PM2_Supporting). This variant was reported in two male siblings with autism who inherited the p.Glu483Ter variant from their unaffected mother (PMID 23352163). In summary, the p.Glu483Ter variant in MECP2 is classified as variant of unknown significance based on the ACMG/AMP criteria (PVS1_Moderate, PM2_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA156430/MONDO:0010726/036

• Frequency: Genomes: not found (cov: 22)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1
• Conservation: PhyloP100: 6.15

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 Uncertain_significance. Variant got 3 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1483G>T	p.Glu495Ter	stop_gained	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1447G>T	p.Glu483Ter	stop_gained	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1483G>T	p.Glu495Ter	stop_gained	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1447G>T	p.Glu483Ter	stop_gained	4/4	1	NM_004992.4	P1
MECP2	ENST00000628176.2	c.*819G>T		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2021

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28263302, 23352163, 24878448, 23352160) -

Rett syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Aug 23, 2023

The p.Glu483Ter variant in MECP2 (NM_004992.4) is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (PVS1_Moderate). The p.Glu483Ter variant in MECP2 is absent from gnomAD (PM2_Supporting). This variant was reported in two male siblings with autism who inherited the p.Glu483Ter variant from their unaffected mother (PMID 23352163). In summary, the p.Glu483Ter variant in MECP2 is classified as variant of unknown significance based on the ACMG/AMP criteria (PVS1_Moderate, PM2_Supporting). -

Autism, susceptibility to, X-linked 3 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 23, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D
Vest4		0.75
GERP RS		4.9

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: rs587777421; hg19: chrX-153295832;