2-148469247-C-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_001378120.1(MBD5):c.1304C>T(p.Ser435Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000087 ( 0 hom. )
Consequence
MBD5
NM_001378120.1 missense
NM_001378120.1 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 7.44
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 Likely_benign. Variant got -5 ACMG points.
BP6
Variant 2-148469247-C-T is Benign according to our data. Variant chr2-148469247-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468769.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=1}.
BS2
High AC in GnomAdExome4 at 127 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MBD5 | NM_001378120.1 | c.1304C>T | p.Ser435Phe | missense_variant | 8/14 | ENST00000642680.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MBD5 | ENST00000642680.2 | c.1304C>T | p.Ser435Phe | missense_variant | 8/14 | NM_001378120.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250384Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135284
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GnomAD4 exome AF: 0.0000869 AC: 127AN: 1461760Hom.: 0 Cov.: 33 AF XY: 0.0000866 AC XY: 63AN XY: 727172
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2018 | The p.S435F variant (also known as c.1304C>T), located in coding exon 4 of the MBD5 gene, results from a C to T substitution at nucleotide position 1304. The serine at codon 435 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Intellectual disability, autosomal dominant 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | - - |
Intellectual disability Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant interpreted as Uncertain significance and reported on 01-31-2020 by Lab or GTR ID 500031. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;L;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;.;.;.;N
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;D
Sift4G
Uncertain
D;.;.;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of glycosylation at S435 (P = 0.0127);Loss of glycosylation at S435 (P = 0.0127);Loss of glycosylation at S435 (P = 0.0127);Loss of glycosylation at S435 (P = 0.0127);Loss of glycosylation at S435 (P = 0.0127);
MVP
MPC
ClinPred
T
GERP RS
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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