rs151204004

Variant names:

• chr2-148458827-G-A
• rs151204004
• NM_001378120.1:c.69G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001378120.1(MBD5):​c.69G>A​(p.Val23Val) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000347 in 1,613,706 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MBD5 NM_001378120.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.24
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-148458827-G-A is Benign according to our data. Variant chr2-148458827-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198228.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00023 (35/152228) while in subpopulation AMR AF = 0.00197 (30/15250). AF 95% confidence interval is 0.00142. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 35 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	NM_001378120.1	MANE Select	c.69G>A	p.Val23Val	synonymous	Exon 5 of 14	NP_001365049.1	A0A2R8YDL9
	MBD5	NM_001438854.1		c.69G>A	p.Val23Val	synonymous	Exon 6 of 15	NP_001425783.1
	MBD5	NM_001438856.1		c.69G>A	p.Val23Val	synonymous	Exon 6 of 15	NP_001425785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	ENST00000642680.2	MANE Select	c.69G>A	p.Val23Val	synonymous	Exon 5 of 14	ENSP00000493871.2	A0A2R8YDL9
	MBD5	ENST00000407073.5	TSL:1	c.69G>A	p.Val23Val	synonymous	Exon 6 of 15	ENSP00000386049.1	Q9P267-1
	MBD5	ENST00000638043.2	TSL:5	c.69G>A	p.Val23Val	synonymous	Exon 5 of 14	ENSP00000490728.2	A0A1B0GW10

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251230 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461478 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727060

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.000380 AC: 17 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111712

Other (OTH) AF: 0.0000663 AC: 4 AN: 60362

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74432

African (AFR) AF: 0.0000962 AC: 4 AN: 41566

American (AMR) AF: 0.00197 AC: 30 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.000589

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 1 (1)
-	-	1	MBD5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		4.2
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs151204004; hg19: chr2-149216396;