3-129436608-C-T

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.1036G>A(p.Glu346Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,056 control chromosomes in the GnomAD database, including 4,120 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E346E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.036 ( 602 hom., cov: 32)

Exomes 𝑓: 0.020 ( 3518 hom. )

Consequence

MBD4
NM_001276270.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.75

Publications

45 publications found

Variant links:

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=0.0010472536).

BP6

Variant 3-129436608-C-T is Benign according to our data. Variant chr3-129436608-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2 link	c.1036G>A	p.Glu346Lys	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.1036G>A	p.Glu346Lys	missense_variant	Exon 3 of 8	1	NM_001276270.2	ENSP00000394080.2		O95243-2

Frequencies

GnomAD3 genomes

AF:

0.0357

AC:

5423

AN:

152114

Hom.:

601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.400

Gnomad SAS

AF:

0.0353

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0583

AC:

14650

AN:

251334

AF XY:

0.0508

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.408

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.00376

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.0200

AC:

29184

AN:

1461824

Hom.:

3518

Cov.:

AF XY:

0.0193

AC XY:

14039

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0199

AC:

666

AN:

33480

American (AMR)

AF:

0.147

AC:

6561

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00463

AC:

121

AN:

26132

East Asian (EAS)

AF:

0.369

AC:

14663

AN:

39686

South Asian (SAS)

AF:

0.0243

AC:

2096

AN:

86248

European-Finnish (FIN)

AF:

0.00382

AC:

204

AN:

53412

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00263

AC:

2925

AN:

1111986

Other (OTH)

AF:

0.0316

AC:

1909

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1469

2938

4406

5875

7344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.0357

AC:

5437

AN:

152232

Hom.:

602

Cov.:

AF XY:

0.0410

AC XY:

3050

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0207

AC:

860

AN:

41562

American (AMR)

AF:

0.131

AC:

2000

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.399

AC:

2056

AN:

5148

South Asian (SAS)

AF:

0.0351

AC:

169

AN:

4818

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00329

AC:

224

AN:

68018

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

217

434

652

869

1086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0199

Hom.:

1039

Bravo

AF:

0.0454

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.0220

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.0509

AC:

6183

Asia WGS

AF:

0.173

AC:

600

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00385

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

This variant is associated with the following publications: (PMID: 16803845, 19469655, 18495292, 23027038) -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Inborn genetic diseases

Benign:1

Oct 18, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.060

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.0020

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.090

.;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.47

T;T;T;T

MetaRNN

Benign

0.0010

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.17

N;N;N;N

PhyloP100

-1.7

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.94

N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.41

T;T;T;T

Sift4G

Benign

0.50

T;T;T;T

Polyphen

0.0060

B;B;B;.

Vest4

0.092

MPC

0.11

ClinPred

0.0022

GERP RS

-3.7

Varity_R

0.064

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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