rs1358383505

Variant names:

• chr2-148483152-A-G
• rs1358383505
• NM_001378120.1:c.2561A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001378120.1(MBD5):​c.2561A>G​(p.Asn854Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,262 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.314
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07607925).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000198 (3/151712) while in subpopulation NFE AF = 0.0000441 (3/67962). AF 95% confidence interval is 0.0000117. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	NM_001378120.1	MANE Select	c.2561A>G	p.Asn854Ser	missense	Exon 9 of 14	NP_001365049.1
	MBD5	NM_001438854.1		c.2561A>G	p.Asn854Ser	missense	Exon 10 of 15	NP_001425783.1
	MBD5	NM_001438856.1		c.2561A>G	p.Asn854Ser	missense	Exon 10 of 15	NP_001425785.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	ENST00000642680.2	MANE Select	c.2561A>G	p.Asn854Ser	missense	Exon 9 of 14	ENSP00000493871.2
	MBD5	ENST00000407073.5	TSL:1	c.2561A>G	p.Asn854Ser	missense	Exon 10 of 15	ENSP00000386049.1
	MBD5	ENST00000638043.2	TSL:5	c.2561A>G	p.Asn854Ser	missense	Exon 9 of 14	ENSP00000490728.2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151712 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461550 Hom.: 1 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151712 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74052

African (AFR) AF: 0.00 AC: 0 AN: 41274

American (AMR) AF: 0.00 AC: 0 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal dominant 1 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.1
DANN	Benign	0.80
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.31
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.073
Sift	Benign	0.40	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.18		Gain of glycosylation at N854 (P = 0.0098)
MVP		0.14
MPC		0.12
ClinPred		0.15	T
GERP RS		-2.9
Varity_R		0.050
gMVP		0.19
Mutation Taster		=96/4	polymorphism

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: rs1358383505; hg19: chr2-149240721;