rs114359726

chr2-148483431-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001378120.1(MBD5):c.2840G>A(p.Gly947Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G947R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.39

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16203389).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD5	NM_001378120.1	c.2840G>A	p.Gly947Glu	missense_variant	9/14	ENST00000642680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD5	ENST00000642680.2	c.2840G>A	p.Gly947Glu	missense_variant	9/14		NM_001378120.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249184 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461730 Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 947 of the MBD5 protein (p.Gly947Glu). This variant is present in population databases (rs114359726, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MBD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 193727). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MBD5 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2014	p.G947E(GGA>GAA):c.2840G>A in exon 10 of the MBD5 gene (NM_018328.4) The G947E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It was identified on 1/167 (.59%) control alleles in individuals of European ancestry in the 1000 Genomes database. The G947E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is highly conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, only deletions and frameshift mutations in MBD5 have been published in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI,EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.057	T;.;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.81	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;.;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D;.;.;D
Sift4G	Uncertain	0.019	D;.;.;T
Polyphen		0.60	P;.;.;.
Vest4		0.76
MVP		0.56
MPC		0.20
ClinPred		0.24	T
GERP RS		5.0
Varity_R		0.25
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114359726; hg19: chr2-149241000;