X-154097665-T-A

Variant names:

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

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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004992.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_004992.4	MANE Plus Clinical	c.-160A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001110792.2	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.-160A>T		5_prime_UTR	Exon 1 of 4	NP_004983.1	D3YJ43

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-160A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-160A>T		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6	P51608-1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Rett syndrome (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.46	T
PhyloP100		1.9
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.35
Sift	Benign	0.22	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.10	B
Vest4		0.84
MutPred		0.64		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;