rs143028540

chr2-148485940-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001378120.1(MBD5):c.3743A>G(p.Gln1248Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000825 in 1,613,954 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (2 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03577733).
• BP6: Variant 2-148485940-A-G is Benign according to our data. Variant chr2-148485940-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 193911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD5	NM_001378120.1	c.3743A>G	p.Gln1248Arg	missense_variant	10/14	ENST00000642680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD5	ENST00000642680.2	c.3743A>G	p.Gln1248Arg	missense_variant	10/14		NM_001378120.1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000510 AC: 128 AN: 251062 Hom.: 0 AF XY: 0.000508 AC XY: 69 AN XY: 135712

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000873

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000842 AC: 1230 AN: 1461632 Hom.: 2 Cov.: 32 AF XY: 0.000836 AC XY: 608 AN XY: 727140

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74488

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000917 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MBD5: BS1 -

Intellectual disability, autosomal dominant 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	MBD5 NM_018328.4 exon 11 p.Gln1015Arg (c.3044A>G): This variant has not been reported in the literature but is present in 0.1% (78/64570) of European alleles in the Genome Aggregation Database, including 1 homozygote (https://gnomad.broadinstitute.org/variant/2-148485940-A-G?dataset=gnomad_r3). This variant is also present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:193911). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 04, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 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. -

MBD5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2022

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.056	T;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.86	D;.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L;.;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.0	N;.;.;N
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;.;.;D
Sift4G	Benign	0.072	T;.;.;T
Polyphen		0.98	D;.;.;D
Vest4		0.87
MVP		0.34
MPC		0.17
ClinPred		0.046	T
GERP RS		5.5
Varity_R		0.27
gMVP		0.64

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

Other links and lift over

dbSNP: rs143028540; hg19: chr2-149243509;