rs2307289

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001276270.2(MBD4):c.1024T>C(p.Ser342Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,052 control chromosomes in the GnomAD database, including 1,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S342L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 380 hom., cov: 32)

Exomes 𝑓: 0.012 ( 914 hom. )

Consequence

MBD4
NM_001276270.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.217

Publications

14 publications found

Variant links:

COSMIC-nc: COSV105073110

Genes affected

MBD4 (HGNC:6919): (methyl-CpG binding domain 4, DNA glycosylase) 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 an MBD domain at the N-terminus that functions both in binding to methylated DNA and in protein interactions and a C-terminal mismatch-specific glycosylase domain that is involved in DNA repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2013]

MBD4 links:

IFT122 (HGNC:13556): (intraflagellar transport 122) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

IFT122 Gene-Disease associations (from GenCC):

cranioectodermal dysplasia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
cranioectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IFT122 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016411841).

BP6

Variant 3-129436620-A-G is Benign according to our data. Variant chr3-129436620-A-G is described in ClinVar as [Benign]. Clinvar id is 1268570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2 link	c.1024T>C	p.Ser342Pro	missense_variant	Exon 3 of 8	ENST00000429544.7	NP_001263199.1	O95243-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7 link	c.1024T>C	p.Ser342Pro	missense_variant	Exon 3 of 8	1	NM_001276270.2	ENSP00000394080.2		O95243-2

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6198

AN:

152116

Hom.:

380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0185

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.0243

AC:

6104

AN:

251338

AF XY:

0.0261

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0155

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00221

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.0119

AC:

17452

AN:

1461818

Hom.:

914

Cov.:

AF XY:

0.0142

AC XY:

10313

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.129

AC:

4331

AN:

33474

American (AMR)

AF:

0.00729

AC:

326

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.0150

AC:

595

AN:

39688

South Asian (SAS)

AF:

0.104

AC:

8951

AN:

86254

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00193

AC:

2150

AN:

1111972

Other (OTH)

AF:

0.0168

AC:

1017

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1040

2080

3119

4159

5199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.0408

AC:

6206

AN:

152234

Hom.:

380

Cov.:

AF XY:

0.0408

AC XY:

3041

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.124

AC:

5163

AN:

41526

American (AMR)

AF:

0.0139

AC:

213

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0184

AC:

AN:

5174

South Asian (SAS)

AF:

0.107

AC:

515

AN:

4826

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00213

AC:

145

AN:

68014

Other (OTH)

AF:

0.0336

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

283

566

849

1132

1415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0177

Hom.:

277

Bravo

AF:

0.0433

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.123

AC:

542

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.0285

AC:

3465

Asia WGS

AF:

0.0800

AC:

277

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MBD4-related disorder

Benign:1

Dec 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.10

.;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.41

T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.34

N;N;N;N

PhyloP100

0.22

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.048

MPC

0.13

ClinPred

0.0030

GERP RS

2.7

Varity_R

0.20

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over