rs140692

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.335+27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,501,376 control chromosomes in the GnomAD database, including 11,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1678 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9630 hom. )

Consequence

MBD4
NM_001276270.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.665

Publications

7 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 (BayesDel_noAF=-0.84).

BP6

Variant 3-129437693-A-G is Benign according to our data. Variant chr3-129437693-A-G is described in ClinVar as Benign. ClinVar VariationId is 1249121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2 link	c.335+27T>C		intron_variant	Intron 2 of 7	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.335+27T>C		intron_variant	Intron 2 of 7	1	NM_001276270.2	ENSP00000394080.2		O95243-2

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20018

AN:

152096

Hom.:

1673

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.167

Gnomad EAS

AF:

0.0813

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.0394

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0944

Gnomad OTH

AF:

0.142

GnomAD2 exomes

AF:

0.116

AC:

29218

AN:

251208

AF XY:

0.123

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.0703

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.0770

Gnomad FIN exome

AF:

0.0394

Gnomad NFE exome

AF:

0.0961

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.108

AC:

145580

AN:

1349162

Hom.:

9630

Cov.:

AF XY:

0.113

AC XY:

76273

AN XY:

677342

show subpopulations

African (AFR)

AF:

0.225

AC:

7001

AN:

31142

American (AMR)

AF:

0.0736

AC:

3284

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

4261

AN:

25460

East Asian (EAS)

AF:

0.0641

AC:

2514

AN:

39198

South Asian (SAS)

AF:

0.246

AC:

20675

AN:

83980

European-Finnish (FIN)

AF:

0.0417

AC:

2223

AN:

53360

Middle Eastern (MID)

AF:

0.159

AC:

885

AN:

5550

European-Non Finnish (NFE)

AF:

0.0970

AC:

97894

AN:

1009326

Other (OTH)

AF:

0.121

AC:

6843

AN:

56556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6264

12528

18792

25056

31320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3672

7344

11016

14688

18360

<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:

0.132

AC:

20047

AN:

152214

Hom.:

1678

Cov.:

AF XY:

0.131

AC XY:

9766

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.217

AC:

9002

AN:

41490

American (AMR)

AF:

0.106

AC:

1614

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

577

AN:

3464

East Asian (EAS)

AF:

0.0807

AC:

419

AN:

5192

South Asian (SAS)

AF:

0.240

AC:

1160

AN:

4828

European-Finnish (FIN)

AF:

0.0394

AC:

419

AN:

10622

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0945

AC:

6427

AN:

68014

Other (OTH)

AF:

0.144

AC:

303

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

868

1736

2603

3471

4339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.130

Hom.:

409

Bravo

AF:

0.138

Asia WGS

AF:

0.205

AC:

715

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.8

(source)

DANN

Benign

0.55

PhyloP100

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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