X-154024879-G-GAT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001110792.2(MECP2):c.*5487_*5488insAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 111,652 control chromosomes in the GnomAD database, including 4 homozygotes. There are 158 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., 158 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.04

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 -10 ACMG points.

• BP6: Variant X-154024879-G-GAT is Benign according to our data. Variant chrX-154024879-G-GAT is described in ClinVar as [Benign]. Clinvar id is 143277.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00511 (571/111652) while in subpopulation NFE AF= 0.00761 (404/53094). AF 95% confidence interval is 0.007. There are 4 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.*5487_*5488insAT		3_prime_UTR_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.*5487_*5488insAT		3_prime_UTR_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.*5487_*5488insAT		3_prime_UTR_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.*5487_*5488insAT		3_prime_UTR_variant	3/3	1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 570 AN: 111603 Hom.: 3 Cov.: 23 AF XY: 0.00467 AC XY: 158 AN XY: 33813

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00946

Gnomad EAS AF: 0.000275

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.0209

Gnomad NFE AF: 0.00761

Gnomad OTH AF: 0.0107

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 295 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 123

Gnomad4 FIN exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00511 AC: 571 AN: 111652 Hom.: 4 Cov.: 23 AF XY: 0.00466 AC XY: 158 AN XY: 33872

Gnomad4 AFR AF: 0.00117

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00946

Gnomad4 EAS AF: 0.000276

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00101

Gnomad4 NFE AF: 0.00761

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.00583 Hom.: 34

Bravo AF: 0.00618

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Oct 11, 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). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 10, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202139104; hg19: chrX-153290330;