chrX-154031559-T-C

Variant names:

• chrX-154031559-T-C
• rs3850326
• NM_001110792.2:c.414-109A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.414-109A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,000,776 control chromosomes in the GnomAD database, including 793 homozygotes. There are 11,739 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (77 hom., 1171 hem., cov: 23)
  • Exomes 𝑓: 0.044 (716 hom. 10568 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.795
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant X-154031559-T-C is Benign according to our data. Variant chrX-154031559-T-C is described in ClinVar as Benign. ClinVar VariationId is 156061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0392 (4354/111086) while in subpopulation NFE AF = 0.0452 (2391/52912). AF 95% confidence interval is 0.0437. There are 77 homozygotes in GnomAd4. There are 1171 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4354 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.414-109A>G		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.378-109A>G		intron_variant	Intron 3 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.414-109A>G		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.378-109A>G		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 4338 AN: 111035 Hom.: 73 Cov.: 23

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0377

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0384

GnomAD4 exome AF: 0.0437 AC: 38853 AN: 889690 Hom.: 716 AF XY: 0.0440 AC XY: 10568 AN XY: 240348

African (AFR) AF: 0.0443 AC: 994 AN: 22423

American (AMR) AF: 0.0131 AC: 443 AN: 33933

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 538 AN: 17736

East Asian (EAS) AF: 0.00811 AC: 237 AN: 29210

South Asian (SAS) AF: 0.0108 AC: 518 AN: 48115

European-Finnish (FIN) AF: 0.0451 AC: 1474 AN: 32693

Middle Eastern (MID) AF: 0.0117 AC: 29 AN: 2484

European-Non Finnish (NFE) AF: 0.0497 AC: 33012 AN: 663741

Other (OTH) AF: 0.0409 AC: 1608 AN: 39355

GnomAD4 genome AF: 0.0392 AC: 4354 AN: 111086 Hom.: 77 Cov.: 23 AF XY: 0.0351 AC XY: 1171 AN XY: 33318

African (AFR) AF: 0.0426 AC: 1300 AN: 30516

American (AMR) AF: 0.0177 AC: 186 AN: 10513

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 85 AN: 2636

East Asian (EAS) AF: 0.0110 AC: 39 AN: 3534

South Asian (SAS) AF: 0.0103 AC: 27 AN: 2625

European-Finnish (FIN) AF: 0.0412 AC: 245 AN: 5945

Middle Eastern (MID) AF: 0.0415 AC: 9 AN: 217

European-Non Finnish (NFE) AF: 0.0452 AC: 2391 AN: 52912

Other (OTH) AF: 0.0479 AC: 72 AN: 1504

Alfa AF: 0.0428 Hom.: 246

Bravo AF: 0.0389

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 Specifications 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). -

not specified Benign:1

Dec 03, 2010

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.040
DANN	Benign	0.30
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism (auto)

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: rs3850326; hg19: chrX-153297010;