Genetic Variant MBD1:p.Pro470Pro (chr18-50273600-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_015846.4(MBD1):c.1410G>A(p.Pro470Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,613,006 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 16 hom. )

Consequence

MBD1
NM_015846.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -1.40

Publications

2 publications found

Variant links:

Genes affected

MBD1 (HGNC:6916): (methyl-CpG binding domain protein 1) The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains multiple domains: MBD at the N-terminus that functions both in binding to methylated DNA and in protein interactions; several CXXC-type zinc finger domains that mediate binding to non-methylated CpG dinucleotides; transcriptional repression domain (TRD) at the C-terminus that is involved in transcription repression and in protein interactions. Numerous alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Feb 2011]

MBD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 18-50273600-C-T is Benign according to our data. Variant chr18-50273600-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 403072.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.4 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MBD1	NM_015846.4	MANE Select	c.1410G>A	p.Pro470Pro	synonymous	Exon 12 of 17	NP_056671.2
MBD1	NM_001323942.2		c.1485G>A	p.Pro495Pro	synonymous	Exon 13 of 17	NP_001310871.1
MBD1	NM_001323947.2		c.1485G>A	p.Pro495Pro	synonymous	Exon 13 of 17	NP_001310876.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MBD1	ENST00000269468.10	TSL:5 MANE Select	c.1410G>A	p.Pro470Pro	synonymous	Exon 12 of 17	ENSP00000269468.5
MBD1	ENST00000590208.5	TSL:1	c.1410G>A	p.Pro470Pro	synonymous	Exon 12 of 16	ENSP00000468785.1
MBD1	ENST00000588937.5	TSL:1	c.1341G>A	p.Pro447Pro	synonymous	Exon 10 of 13	ENSP00000467763.1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00307

AC:

767

AN:

249934

AF XY:

0.00307

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.00462

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00365

AC:

5337

AN:

1460680

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

2619

AN XY:

726660

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33476

American (AMR)

AF:

0.000581

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00582

AC:

152

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00767

AC:

401

AN:

52278

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00411

AC:

4571

AN:

1111974

Other (OTH)

AF:

0.00263

AC:

159

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

369

738

1108

1477

1846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00249

AC:

380

AN:

152326

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41582

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00668

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00360

AC:

245

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00350

Hom.:

Bravo

AF:

0.00210

EpiCase

AF:

0.00354

EpiControl

AF:

0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 39/13006=0.2%

MBD1-related disorder

Benign:1

Apr 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.6

(source)

DANN

Benign

0.63

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over