Genetic Variant MBD1:p.Cys650Cys (chr18-50269647-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001323942.2(MBD1):c.2025C>T(p.Cys675Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 745,532 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 18 hom. )

Consequence

MBD1
NM_001323942.2 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.917

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 18-50269647-G-A is Benign according to our data. Variant chr18-50269647-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060893.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.917 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323942.2. 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.*204C>T		3_prime_UTR	Exon 17 of 17	NP_056671.2
MBD1	NM_001323942.2		c.2025C>T	p.Cys675Cys	synonymous	Exon 17 of 17	NP_001310871.1
MBD1	NM_001323947.2		c.1980C>T	p.Cys660Cys	synonymous	Exon 17 of 17	NP_001310876.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MBD1	ENST00000590208.5	TSL:1	c.1950C>T	p.Cys650Cys	synonymous	Exon 16 of 16	ENSP00000468785.1
MBD1	ENST00000588937.5	TSL:1	c.1743C>T	p.Cys581Cys	synonymous	Exon 13 of 13	ENSP00000467763.1
MBD1	ENST00000269468.10	TSL:5 MANE Select	c.*204C>T		3_prime_UTR	Exon 17 of 17	ENSP00000269468.5

Frequencies

GnomAD3 genomes

AF:

0.00458

AC:

697

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00786

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00495

AC:

967

AN:

195234

AF XY:

0.00501

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.000221

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00655

Gnomad NFE exome

AF:

0.00855

Gnomad OTH exome

AF:

0.00484

GnomAD4 exome

AF:

0.00578

AC:

3427

AN:

593260

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

1808

AN XY:

321540

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

16836

American (AMR)

AF:

0.00226

AC:

AN:

38536

Ashkenazi Jewish (ASJ)

AF:

0.000246

AC:

AN:

20312

East Asian (EAS)

AF:

0.00

AC:

AN:

34476

South Asian (SAS)

AF:

0.00141

AC:

AN:

65930

European-Finnish (FIN)

AF:

0.00631

AC:

322

AN:

51028

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00831

AC:

2746

AN:

330260

Other (OTH)

AF:

0.00475

AC:

151

AN:

31782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

227

453

680

906

1133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00458

AC:

697

AN:

152272

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

326

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41554

American (AMR)

AF:

0.00229

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00556

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00786

AC:

535

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00596

Hom.:

Bravo

AF:

0.00435

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MBD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Computational scores

Splicing

Publications

Other links and lift over