X-154021863-TG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001110792.2(MECP2):c.*8503del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (69 hom., 730 hem., cov: 16)
  • Exomes 𝑓: 0.040 (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: 1.18

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-154021863-TG-T is Benign according to our data. Variant chrX-154021863-TG-T is described in ClinVar as [Benign]. Clinvar id is 143288.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154021863-TG-T is described in Lovd as [Benign]. Variant chrX-154021863-TG-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.*8503del		3_prime_UTR_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.*8503del		3_prime_UTR_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.*8503del		3_prime_UTR_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.*8503del		3_prime_UTR_variant	3/3	1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 2902 AN: 72406 Hom.: 69 Cov.: 16 AF XY: 0.0472 AC XY: 730 AN XY: 15476

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00647

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.0281

Gnomad NFE AF: 0.00975

Gnomad OTH AF: 0.0300

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0403 AC: 6 AN: 149 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 49

Gnomad4 FIN exome AF: 0.0405

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0400 AC: 2900 AN: 72429 Hom.: 69 Cov.: 16 AF XY: 0.0471 AC XY: 730 AN XY: 15491

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.00647

Gnomad4 EAS AF: 0.0313

Gnomad4 SAS AF: 0.0334

Gnomad4 FIN AF: 0.0450

Gnomad4 NFE AF: 0.00975

Gnomad4 OTH AF: 0.0296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 10, 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). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

Computational scores

Source: dbNSFP v4.3

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: rs267608360; hg19: chrX-153287314;