chr3-129436608-C-T

Position:

chr3-129436608-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000429544.7(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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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
ENST00000429544.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.75

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 -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 id 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/exons	MANE	Protein	UniProt
MBD4	NM_001276270.2 linkuse as main transcript	c.1036G>A	p.Glu346Lys	missense_variant	3/8	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7 linkuse as main transcript	c.1036G>A	p.Glu346Lys	missense_variant	3/8	1	NM_001276270.2	ENSP00000394080	A2	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

GnomAD3 exomes

AF:

0.0583

AC:

14650

AN:

251334

Hom.:

2045

AF XY:

0.0508

AC XY:

6907

AN XY:

135850

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 SAS exome

AF:

0.0238

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

Gnomad4 AFR exome

AF:

0.0199

Gnomad4 AMR exome

AF:

0.147

Gnomad4 ASJ exome

AF:

0.00463

Gnomad4 EAS exome

AF:

0.369

Gnomad4 SAS exome

AF:

0.0243

Gnomad4 FIN exome

AF:

0.00382

Gnomad4 NFE exome

AF:

0.00263

Gnomad4 OTH exome

AF:

0.0316

GnomAD4 genome

AF:

0.0357

AC:

5437

AN:

152232

Hom.:

602

Cov.:

AF XY:

0.0410

AC XY:

3050

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0207

Gnomad4 AMR

AF:

0.131

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.399

Gnomad4 SAS

AF:

0.0351

Gnomad4 FIN

AF:

0.00405

Gnomad4 NFE

AF:

0.00329

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.0176

Hom.:

705

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 16803845, 19469655, 18495292, 23027038) -

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

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

MutationTaster

Benign

1.0

P;P;P;P;P

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

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