rs187614438

Variant names:

• chrX-154029506-A-C
• rs187614438
• NM_001110792.2:c.*861T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.*861T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 112,583 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 56 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 56 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.168
• Publications: 0 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00188 (210/111946) while in subpopulation NFE AF = 0.00355 (188/52985). AF 95% confidence interval is 0.00313. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 210 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*861T>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*861T>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.*861T>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.*861T>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000630151.3	c.*861T>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 210 AN: 111893 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000843

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00355

Gnomad OTH AF: 0.00133

GnomAD4 exome AF: 0.00157 AC: 1 AN: 637 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 179

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 51

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 11

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 279

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00376 AC: 1 AN: 266

Other (OTH) AF: 0.00 AC: 0 AN: 19

GnomAD4 genome AF: 0.00188 AC: 210 AN: 111946 Hom.: 0 Cov.: 23 AF XY: 0.00164 AC XY: 56 AN XY: 34130

African (AFR) AF: 0.000260 AC: 8 AN: 30795

American (AMR) AF: 0.000842 AC: 9 AN: 10693

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2677

European-Finnish (FIN) AF: 0.000325 AC: 2 AN: 6152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00355 AC: 188 AN: 52985

Other (OTH) AF: 0.00131 AC: 2 AN: 1527

Alfa AF: 0.00243 Hom.: 15

Bravo AF: 0.00208

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 01, 2007

RettBASE

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Rett syndrome Benign:1

Aug 14, 2023

Centre for Population Genomics, CPG

Significance: Benign

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 to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0 , this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.62
DANN	Benign	0.69
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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: rs187614438; hg19: chrX-153294957;