rs17435

Variant names:

• chrX-154046529-T-A
• rs17435
• NM_001110792.2:c.63-13972A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154046529-T-A
• chrX-154046529-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001110792.2(MECP2):​c.63-13972A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.64 (17489 hom., 19996 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.09

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-154046529-T-A is Benign according to our data. Variant chrX-154046529-T-A is described in ClinVar as [Benign]. Clinvar id is 3602068.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.63-13972A>T		intron_variant	Intron 1 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.27-13972A>T		intron_variant	Intron 2 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.63-13972A>T		intron_variant	Intron 1 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.27-13972A>T		intron_variant	Intron 2 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.636 AC: 69632 AN: 109564 Hom.: 17498 Cov.: 22 AF XY: 0.627 AC XY: 19974 AN XY: 31856

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.965

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.635 AC: 69629 AN: 109618 Hom.: 17489 Cov.: 22 AF XY: 0.626 AC XY: 19996 AN XY: 31920

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.535

Gnomad4 ASJ AF: 0.737

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.802

Gnomad4 NFE AF: 0.806

Gnomad4 OTH AF: 0.592

Alfa AF: 0.547 Hom.: 2350

Bravo AF: 0.602

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Benign:1

Dec 02, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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. 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). Synonymous or intronic variant where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1). Synonymous or intronic variant outside donor and acceptor splice regions where splicing prediction algorithms do not support significant splicing alteration (spliceAI score <=0.1) (BP4, BP7). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.33
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17435; hg19: chrX-153311980;