rs3850326

chrX-154031559-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_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:3 O:1
• Conservation: PhyloP100: -0.795

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 73 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.414-109A>G		intron_variant		ENST00000453960.7
MECP2	NM_004992.4	c.378-109A>G		intron_variant		ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.378-109A>G		intron_variant		1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.414-109A>G		intron_variant		1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 4338 AN: 111035 Hom.: 73 Cov.: 23 AF XY: 0.0351 AC XY: 1167 AN XY: 33257

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

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.00811

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0451

Gnomad4 NFE exome AF: 0.0497

Gnomad4 OTH exome AF: 0.0409

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

Gnomad4 AFR AF: 0.0426

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0322

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0103

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0428 Hom.: 246

Bravo AF: 0.0389

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, flagged submission	literature only	RettBASE	-	- -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Dec 03, 2010

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Aug 14, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.040
Dann	Benign	0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs3850326; hg19: chrX-153297010;