rs61754448

Variant names:

• chrX-154032295-C-A
• rs61754448
• NM_001110792.2:c.325G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001110792.2(MECP2):​c.325G>T​(p.Asp109Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D109E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.78
• Publications: 6 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant X-154032295-C-A is Pathogenic according to our data. Variant chrX-154032295-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 143517.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.325G>T	p.Asp109Tyr	missense	Exon 2 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.289G>T	p.Asp97Tyr	missense	Exon 3 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.10G>T	p.Asp4Tyr	missense	Exon 4 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.325G>T	p.Asp109Tyr	missense	Exon 2 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.289G>T	p.Asp97Tyr	missense	Exon 3 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.289G>T	p.Asp97Tyr	missense	Exon 3 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Rett syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.85		Gain of phosphorylation at D97 (P = 0.0297)
MVP		1.0
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		0.018	Neutral
Varity_R		0.95
gMVP		0.98
Mutation Taster		=0/100	disease causing

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: rs61754448; hg19: chrX-153297746;