3-129436827-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.817G>A(p.Ala273Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 1,614,010 control chromosomes in the GnomAD database, including 6,177 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. A273A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.077 ( 507 hom., cov: 32)

Exomes 𝑓: 0.085 ( 5670 hom. )

Consequence

MBD4
NM_001276270.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.275

Publications

31 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=0.0015313923).

BP6

Variant 3-129436827-C-T is Benign according to our data. Variant chr3-129436827-C-T is described in ClinVar as Benign. ClinVar VariationId is 1236752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2 link	c.817G>A	p.Ala273Thr	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.817G>A	p.Ala273Thr	missense_variant	Exon 3 of 8	1	NM_001276270.2	ENSP00000394080.2		O95243-2

Frequencies

GnomAD3 genomes

AF:

0.0768

AC:

11681

AN:

152144

Hom.:

504

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0674

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0770

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.0620

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0381

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0835

Gnomad OTH

AF:

0.0947

GnomAD2 exomes

AF:

0.0801

AC:

20148

AN:

251388

AF XY:

0.0839

show subpopulations

Gnomad AFR exome

AF:

0.0685

Gnomad AMR exome

AF:

0.0562

Gnomad ASJ exome

AF:

0.163

Gnomad EAS exome

AF:

0.0613

Gnomad FIN exome

AF:

0.0370

Gnomad NFE exome

AF:

0.0841

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0848

AC:

124002

AN:

1461748

Hom.:

5670

Cov.:

AF XY:

0.0865

AC XY:

62928

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.0686

AC:

2297

AN:

33480

American (AMR)

AF:

0.0584

AC:

2612

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

4263

AN:

26134

East Asian (EAS)

AF:

0.0493

AC:

1959

AN:

39698

South Asian (SAS)

AF:

0.112

AC:

9658

AN:

86256

European-Finnish (FIN)

AF:

0.0389

AC:

2078

AN:

53360

Middle Eastern (MID)

AF:

0.126

AC:

727

AN:

5768

European-Non Finnish (NFE)

AF:

0.0853

AC:

94807

AN:

1111934

Other (OTH)

AF:

0.0927

AC:

5601

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

7107

14213

21320

28426

35533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3564

7128

10692

14256

17820

<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:

0.0768

AC:

11693

AN:

152262

Hom.:

507

Cov.:

AF XY:

0.0761

AC XY:

5661

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0674

AC:

2801

AN:

41552

American (AMR)

AF:

0.0769

AC:

1176

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

558

AN:

3472

East Asian (EAS)

AF:

0.0616

AC:

319

AN:

5182

South Asian (SAS)

AF:

0.104

AC:

499

AN:

4820

European-Finnish (FIN)

AF:

0.0381

AC:

404

AN:

10602

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0835

AC:

5680

AN:

68020

Other (OTH)

AF:

0.0961

AC:

203

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

557

1115

1672

2230

2787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0631

Hom.:

1610

Bravo

AF:

0.0792

TwinsUK

AF:

0.0747

AC:

277

ALSPAC

AF:

0.0771

AC:

297

ESP6500AA

AF:

0.0667

AC:

294

ESP6500EA

AF:

0.0885

AC:

761

ExAC

AF:

0.0810

AC:

9840

Asia WGS

AF:

0.0990

AC:

347

AN:

3478

EpiCase

AF:

0.0949

EpiControl

AF:

0.0978

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 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 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

0.070

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.12

.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.62

T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.1

L;L;L;L

PhyloP100

0.28

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.90

N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.30

T;T;T;T

Sift4G

Benign

0.68

T;T;T;T

Polyphen

0.041

B;B;B;.

Vest4

0.011

MPC

0.097

ClinPred

0.0012

GERP RS

-0.94

Varity_R

0.093

gMVP

0.15

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