rs10497031

Variant names:

• chr2-148161266-A-G
• rs10497031
• NM_001378120.1:c.-924-17434A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378120.1(MBD5):​c.-924-17434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 152,234 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (648 hom., cov: 32)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 2 publications found

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]

MBD5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378120.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	NM_001378120.1	MANE Select	c.-924-17434A>G		intron	N/A	NP_001365049.1
	MBD5	NM_001438854.1		c.-924-17434A>G		intron	N/A	NP_001425783.1
	MBD5	NM_001438856.1		c.-924-17434A>G		intron	N/A	NP_001425785.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	ENST00000642680.2	MANE Select	c.-924-17434A>G		intron	N/A	ENSP00000493871.2
	MBD5	ENST00000407073.5	TSL:1	c.-924-17434A>G		intron	N/A	ENSP00000386049.1
	MBD5	ENST00000638043.2	TSL:5	c.-924-17434A>G		intron	N/A	ENSP00000490728.2

Frequencies

GnomAD3 genomes AF: 0.0876 AC: 13329 AN: 152116 Hom.: 646 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.0876 AC: 13334 AN: 152234 Hom.: 648 Cov.: 32 AF XY: 0.0869 AC XY: 6465 AN XY: 74422

African (AFR) AF: 0.0427 AC: 1776 AN: 41558

American (AMR) AF: 0.0860 AC: 1315 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3470

East Asian (EAS) AF: 0.102 AC: 526 AN: 5170

South Asian (SAS) AF: 0.142 AC: 686 AN: 4820

European-Finnish (FIN) AF: 0.0659 AC: 699 AN: 10608

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7362 AN: 68004

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.0974 Hom.: 588

Bravo AF: 0.0864

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10497031; hg19: chr2-148918835;