rs587783132

Variant names:

• chrX-154097665-T-A
• rs587783132
• NM_004992.4:c.-160A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP4 PM6_Strong PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The p.Met1Leu variant in MECP2 (NM_004992.4) 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 has been observed in 4 individuals with clinical features of Rett syndrome (PMID:16225173, 19365833, GeneDx Internal Database) (PS4_moderate). The p.Met1Leu variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Met1Leu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PP4, PM2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274666/MONDO:0010726/036

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_004992.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 1.87
• Publications: 12 publications found

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]

MECP2 Gene-Disease associations (from GenCC):

• chromosome Xq28 duplication syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_004992.4	c.-160A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1
MECP2	NM_001110792.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.-160A>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.-160A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000453960.7	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.-160A>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_004992.4	ENSP00000301948.6

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

African (AFR) AF: 0.00 AC: 0 AN: 19582

American (AMR) AF: 0.00 AC: 0 AN: 15389

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12477

East Asian (EAS) AF: 0.00 AC: 0 AN: 22316

South Asian (SAS) AF: 0.00 AC: 0 AN: 29972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21163

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3157

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 748930

Other (OTH) AF: 0.00 AC: 0 AN: 36425

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

Oct 30, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Met1Leu variant in MECP2 (NM_004992.4) 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 has been observed in 4 individuals with clinical features of Rett syndrome (PMID: 16225173, 19365833, GeneDx Internal Database) (PS4_moderate). The p.Met1Leu variant in MECP2 is absent from gnomAD (PM2_supporting). In summary, the p.Met1Leu variant in MECP2 is classified as Likely Pathogenic for Rett syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PP4, PM2_supporting). -

Feb 18, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Nov 05, 2009

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Pathogenic:2

Sep 11, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)." -

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
PhyloP100		1.9
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
PromoterAI		-0.74	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.32
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783132; hg19: chrX-153363122;