rs3027915

Variant names:

• chrX-154022511-T-G
• rs3027915
• NM_001110792.2:c.*7856A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.*7856A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 112,246 control chromosomes in the GnomAD database, including 24 homozygotes. There are 593 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (24 hom., 593 hem., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.124

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-154022511-T-G is Benign according to our data. Variant chrX-154022511-T-G is described in ClinVar as [Benign]. Clinvar id is 143283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154022511-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0185 (2081/112246) while in subpopulation NFE AF= 0.0271 (1442/53138). AF 95% confidence interval is 0.026. There are 24 homozygotes in gnomad4. There are 593 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*7856A>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*7856A>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960	c.*7856A>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391	c.*7856A>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2083 AN: 112195 Hom.: 24 Cov.: 24 AF XY: 0.0173 AC XY: 593 AN XY: 34351

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00589

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0377

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0192

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 17 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 9

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0185 AC: 2081 AN: 112246 Hom.: 24 Cov.: 24 AF XY: 0.0172 AC XY: 593 AN XY: 34412

Gnomad4 AFR AF: 0.00375

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.0318

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00591

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0223 Hom.: 145

Bravo AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Benign:1

Oct 11, 2023

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

not specified Benign:1

Mar 10, 2010

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.97
DANN	Benign	0.71

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: rs3027915; hg19: chrX-153287962;