3-129431542-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001276270.2(MBD4):c.1684G>C(p.Asp562His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,613,132 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0074 ( 68 hom. )

Consequence

MBD4
NM_001276270.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009672582).

BP6

Variant 3-129431542-C-G is Benign according to our data. Variant chr3-129431542-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218624.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00525 (799/152302) while in subpopulation SAS AF= 0.0118 (57/4828). AF 95% confidence interval is 0.00936. There are 3 homozygotes in gnomad4. There are 363 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD4	NM_001276270.2 link	c.1684G>C	p.Asp562His	missense_variant	Exon 8 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.1684G>C	p.Asp562His	missense_variant	Exon 8 of 8	1	NM_001276270.2	ENSP00000394080.2		O95243-2

Frequencies

GnomAD3 genomes

AF:

0.00526

AC:

800

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00782

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00530

AC:

1331

AN:

251134

Hom.:

AF XY:

0.00583

AC XY:

792

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.00341

Gnomad ASJ exome

AF:

0.00814

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00970

Gnomad FIN exome

AF:

0.000327

Gnomad NFE exome

AF:

0.00668

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.00739

AC:

10789

AN:

1460830

Hom.:

Cov.:

AF XY:

0.00757

AC XY:

5501

AN XY:

726772

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00340

Gnomad4 ASJ exome

AF:

0.00827

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0110

Gnomad4 FIN exome

AF:

0.000492

Gnomad4 NFE exome

AF:

0.00800

Gnomad4 OTH exome

AF:

0.00779

GnomAD4 genome

AF:

0.00525

AC:

799

AN:

152302

Hom.:

Cov.:

AF XY:

0.00487

AC XY:

363

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00483

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0118

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00782

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00695

Hom.:

Bravo

AF:

0.00551

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00539

AC:

654

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00856

EpiControl

AF:

0.00812

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with multiple miscarriages and with uveal melanoma (PMID: 25504873, 32421892); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27932076, 23195996, 16418580, 36835215, 26503472, 12935920, 32421892, 32227657, 29293537, 20052722, 25504873) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBD4: BP4, BS1, BS2 -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Mar 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 29, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

.;L;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.18

MVP

0.46

MPC

0.55

ClinPred

0.016

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over