rs267608326

chrX-154030274-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001110792.2(MECP2):c.*93G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,155,451 control chromosomes in the GnomAD database, including 1 homozygotes. There are 290 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., 35 hem., cov: 23)
  • Exomes 𝑓: 0.00090 (1 hom. 255 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.03

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-154030274-C-T is Benign according to our data. Variant chrX-154030274-C-T is described in ClinVar as [Benign]. Clinvar id is 143296.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154030274-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000903 (943/1043888) while in subpopulation NFE AF= 0.000841 (668/794671). AF 95% confidence interval is 0.000787. There are 1 homozygotes in gnomad4_exome. There are 255 alleles in male gnomad4_exome subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 35 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.*93G>A		3_prime_UTR_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.*93G>A		3_prime_UTR_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.*93G>A		3_prime_UTR_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.*93G>A		3_prime_UTR_variant	3/3	1	NM_001110792.2
MECP2	ENST00000628176.2	c.*926G>A		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.000699 AC: 78 AN: 111511 Hom.: 0 Cov.: 23 AF XY: 0.00104 AC XY: 35 AN XY: 33699

Gnomad AFR AF: 0.000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000764

Gnomad FIN AF: 0.00413

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000547

Gnomad OTH AF: 0.000667

GnomAD3 exomes AF: 0.00115 AC: 206 AN: 179250 Hom.: 0 AF XY: 0.00103 AC XY: 67 AN XY: 64886

Gnomad AFR exome AF: 0.000631

Gnomad AMR exome AF: 0.000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000294

Gnomad SAS exome AF: 0.000216

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000903 AC: 943 AN: 1043888 Hom.: 1 Cov.: 23 AF XY: 0.000796 AC XY: 255 AN XY: 320210

Gnomad4 AFR exome AF: 0.000357

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000267

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.00466

Gnomad4 NFE exome AF: 0.000841

Gnomad4 OTH exome AF: 0.000973

GnomAD4 genome AF: 0.000699 AC: 78 AN: 111563 Hom.: 0 Cov.: 23 AF XY: 0.00104 AC XY: 35 AN XY: 33761

Gnomad4 AFR AF: 0.000488

Gnomad4 AMR AF: 0.000568

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000767

Gnomad4 FIN AF: 0.00413

Gnomad4 NFE AF: 0.000547

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.000918 Hom.: 5

Bravo AF: 0.000499

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

Dec 05, 2013

- -

Rett syndrome Benign:1

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267608326; hg19: chrX-153295725;