rs114314967

Positions:

chr2-148469973-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378120.1(MBD5):c.2030G>A(p.Ser677Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,613,950 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 10 hom. )

Consequence

MBD5
NM_001378120.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 6.80

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047388375).

BP6

Variant 2-148469973-G-A is Benign according to our data. Variant chr2-148469973-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-148469973-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00201 (306/152300) while in subpopulation AMR AF= 0.00347 (53/15294). AF 95% confidence interval is 0.00272. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 306 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD5	NM_001378120.1 linkuse as main transcript	c.2030G>A	p.Ser677Asn	missense_variant	8/14	ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2 linkuse as main transcript	c.2030G>A	p.Ser677Asn	missense_variant	8/14		NM_001378120.1	ENSP00000493871.2		A0A2R8YDL9

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00229

AC:

574

AN:

250672

Hom.:

AF XY:

0.00249

AC XY:

337

AN XY:

135438

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00657

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00331

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00240

AC:

3511

AN:

1461650

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1840

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00681

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00202

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00246

Gnomad4 OTH exome

AF:

0.00384

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

152300

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00347

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.00242

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00246

AC:

299

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2018	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	MBD5: BP4, BS1, BS2 -

Intellectual disability, autosomal dominant 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

MBD5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

T;.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.73

T;.;T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.60

N;.;.;N;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.070

N;.;.;.;N

REVEL

Benign

0.12

Sift

Benign

0.15

T;.;.;.;T

Sift4G

Benign

0.17

T;.;.;T;T

Polyphen

0.0

B;.;.;B;.

Vest4

0.31

MVP

0.19

MPC

0.29

ClinPred

0.027

GERP RS

4.0

Varity_R

0.13

gMVP

0.21

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over