chrX-154030268-G-GT

Position:

• chrX-154030268-G-GT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.*98dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,148,758 control chromosomes in the GnomAD database, including 9 homozygotes. There are 816 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., 108 hem., cov: 22)
  • Exomes 𝑓: 0.0023 (6 hom. 708 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.16

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 -16 ACMG points.

• BP6: Variant X-154030268-G-GT is Benign according to our data. Variant chrX-154030268-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 143297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00391 (437/111695) while in subpopulation AFR AF= 0.00826 (254/30743). AF 95% confidence interval is 0.00743. There are 3 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*98dupA		3_prime_UTR_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*98dupA		3_prime_UTR_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960	c.*98dupA		3_prime_UTR_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391	c.*98dupA		3_prime_UTR_variant	4/4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000628176	c.*931dupA		3_prime_UTR_variant	5/5	3		ENSP00000486978.1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 438 AN: 111640 Hom.: 3 Cov.: 22 AF XY: 0.00319 AC XY: 108 AN XY: 33818

Gnomad AFR AF: 0.00828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00152

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.00202

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.00239 AC: 424 AN: 177362 Hom.: 1 AF XY: 0.00208 AC XY: 133 AN XY: 63908

Gnomad AFR exome AF: 0.00925

Gnomad AMR exome AF: 0.00349

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000739

Gnomad SAS exome AF: 0.00202

Gnomad FIN exome AF: 0.000135

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00225 AC: 2337 AN: 1037063 Hom.: 6 Cov.: 22 AF XY: 0.00223 AC XY: 708 AN XY: 317559

Gnomad4 AFR exome AF: 0.00860

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.0000667

Gnomad4 SAS exome AF: 0.00222

Gnomad4 FIN exome AF: 0.000128

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.00391 AC: 437 AN: 111695 Hom.: 3 Cov.: 22 AF XY: 0.00319 AC XY: 108 AN XY: 33883

Gnomad4 AFR AF: 0.00826

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00153

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00202

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.00327 Hom.: 24

Bravo AF: 0.00499

Asia WGS AF: 0.00159 AC: 4 AN: 2522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Feb 18, 2024	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 3.0, 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 3.0 (BA1). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Dec 05, 2013

- -

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: rs267608341; hg19: chrX-153295719;