rs145475623

Variant names:

• chr2-148489474-C-T
• rs145475623
• NM_001378120.1:c.3842C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378120.1(MBD5):​c.3842C>T​(p.Thr1281Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000645 in 1,614,206 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (3 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7
• Conservation: PhyloP100: 3.14
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0380328).
• BP6: Variant 2-148489474-C-T is Benign according to our data. Variant chr2-148489474-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206095.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152318) while in subpopulation NFE AF = 0.000676 (46/68032). AF 95% confidence interval is 0.000521. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 53 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.3842C>T	p.Thr1281Ile	missense	Exon 11 of 14	NP_001365049.1	A0A2R8YDL9
	MBD5	NM_001438854.1		c.3842C>T	p.Thr1281Ile	missense	Exon 12 of 15	NP_001425783.1
	MBD5	NM_001438856.1		c.3842C>T	p.Thr1281Ile	missense	Exon 12 of 15	NP_001425785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	ENST00000642680.2	MANE Select	c.3842C>T	p.Thr1281Ile	missense	Exon 11 of 14	ENSP00000493871.2	A0A2R8YDL9
	MBD5	ENST00000407073.5	TSL:1	c.3143C>T	p.Thr1048Ile	missense	Exon 12 of 15	ENSP00000386049.1	Q9P267-1
	MBD5	ENST00000638043.2	TSL:5	c.3143C>T	p.Thr1048Ile	missense	Exon 11 of 14	ENSP00000490728.2	A0A1B0GW10

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000481 AC: 121 AN: 251428 AF XY: 0.000515

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000950

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000676 AC: 988 AN: 1461888 Hom.: 3 Cov.: 32 AF XY: 0.000701 AC XY: 510 AN XY: 727246

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000833 AC: 926 AN: 1112010

Other (OTH) AF: 0.000679 AC: 41 AN: 60396

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74468

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68032

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000743 Hom.: 2

Bravo AF: 0.000351

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	Intellectual disability, autosomal dominant 1 (1)
1	-	-	MBD5 associated neurodevelopmental disorder (1)
-	-	1	MBD5-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.045
Sift	Benign	0.18	T
Sift4G	Benign	0.11	T
Polyphen		0.0040	B
Vest4		0.23
MVP		0.10
MPC		0.17
ClinPred		0.020	T
GERP RS		5.9
Varity_R		0.10
gMVP		0.15
Mutation Taster		=94/6	disease causing (ClinVar)

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: rs145475623; hg19: chr2-149247043;