X-154029974-C-T

Position:

• chrX-154029974-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.*393G>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 0.00149 in 232,910 control chromosomes in the GnomAD database, including 2 homozygotes. There are 119 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., 43 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (1 hom. 76 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.38

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=-0.91).
• BP6: Variant X-154029974-C-T is Benign according to our data. Variant chrX-154029974-C-T is described in ClinVar as [Benign]. Clinvar id is 143269.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154029974-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00122 (136/111625) while in subpopulation SAS AF= 0.00525 (14/2668). AF 95% confidence interval is 0.00317. There are 1 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 43 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.*393G>A		3_prime_UTR_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.*393G>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.*393G>A		3_prime_UTR_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.*393G>A		3_prime_UTR_variant	3/3	1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 135 AN: 111575 Hom.: 1 Cov.: 23 AF XY: 0.00124 AC XY: 42 AN XY: 33771

Gnomad AFR AF: 0.000523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000757

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000563

Gnomad SAS AF: 0.00523

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00175 AC: 212 AN: 121285 Hom.: 1 Cov.: 0 AF XY: 0.00218 AC XY: 76 AN XY: 34867

Gnomad4 AFR exome AF: 0.000984

Gnomad4 AMR exome AF: 0.000487

Gnomad4 ASJ exome AF: 0.000314

Gnomad4 EAS exome AF: 0.000377

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.000926

GnomAD4 genome AF: 0.00122 AC: 136 AN: 111625 Hom.: 1 Cov.: 23 AF XY: 0.00127 AC XY: 43 AN XY: 33831

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.000756

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000565

Gnomad4 SAS AF: 0.00525

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00162 Hom.: 11

Bravo AF: 0.000937

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

Nov 01, 2007

- -

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.82

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: rs267608361; hg19: chrX-153295425;