rs199626531
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_001378120.1(MBD5):c.3952G>A(p.Val1318Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
MBD5
NM_001378120.1 missense
NM_001378120.1 missense
Scores
1
2
16
Clinical Significance
Conservation
PhyloP100: 6.16
Genes affected
MBD5 (HGNC:20444): (methyl-CpG binding domain protein 5) This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13518816).
BP6
?
Variant 2-148489584-G-A is Benign according to our data. Variant chr2-148489584-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 279846.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
BS2
?
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MBD5 | NM_001378120.1 | c.3952G>A | p.Val1318Ile | missense_variant | 11/14 | ENST00000642680.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MBD5 | ENST00000642680.2 | c.3952G>A | p.Val1318Ile | missense_variant | 11/14 | NM_001378120.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251440Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135886
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727246
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74314
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | MBD5 NM_018328.4 exon 12 p.Val1085Ile (c.3253G>A): This variant has not been reported in the literature but is present in 12/126680 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-149247153-G-A). This variant is present in ClinVar (Variation ID:279846). This variant amino acid isoleucine (Ile) is present in 3 mammals but is well conserved among evolutionarily distant species. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2023 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
Intellectual Disability, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N
REVEL
Benign
Sift
Benign
D;.;.;D
Sift4G
Benign
T;.;.;T
Polyphen
B;.;.;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at