rs140696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001276270.2(MBD4):c.1395C>T(p.Gly465Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,613,452 control chromosomes in the GnomAD database, including 11,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1677 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10307 hom. )

Consequence

MBD4
NM_001276270.2 splice_region, synonymous

Scores

Splicing: ADA: 0.000009672

Clinical Significance

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

Conservation

PhyloP100: -1.23

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 3-129433246-G-A is Benign according to our data. Variant chr3-129433246-G-A is described in ClinVar as [Benign]. Clinvar id is 1262431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.23 with no splicing effect.

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.1395C>T	p.Gly465Gly	splice_region_variant, synonymous_variant	Exon 6 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.1395C>T	p.Gly465Gly	splice_region_variant, synonymous_variant	Exon 6 of 8	1	NM_001276270.2	ENSP00000394080.2		O95243-2

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20023

AN:

152024

Hom.:

1672

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:

0.0814

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.0397

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0944

Gnomad OTH

AF:

0.143

GnomAD3 exomes

AF:

0.116

AC:

29233

AN:

251420

Hom.:

2324

AF XY:

0.123

AC XY:

16705

AN XY:

135892

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 SAS exome

AF:

0.248

Gnomad FIN exome

AF:

0.0394

Gnomad NFE exome

AF:

0.0961

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.108

AC:

157976

AN:

1461310

Hom.:

10307

Cov.:

AF XY:

0.113

AC XY:

81881

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.225

Gnomad4 AMR exome

AF:

0.0736

Gnomad4 ASJ exome

AF:

0.168

Gnomad4 EAS exome

AF:

0.0646

Gnomad4 SAS exome

AF:

0.246

Gnomad4 FIN exome

AF:

0.0417

Gnomad4 NFE exome

AF:

0.0976

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.132

AC:

20052

AN:

152142

Hom.:

1677

Cov.:

AF XY:

0.131

AC XY:

9777

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.217

Gnomad4 AMR

AF:

0.106

Gnomad4 ASJ

AF:

0.167

Gnomad4 EAS

AF:

0.0808

Gnomad4 SAS

AF:

0.240

Gnomad4 FIN

AF:

0.0397

Gnomad4 NFE

AF:

0.0945

Gnomad4 OTH

AF:

0.144

Alfa

AF:

0.108

Hom.:

1725

Bravo

AF:

0.138

Asia WGS

AF:

0.204

AC:

714

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.112

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 04, 2021

GeneDx

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

- -

Sep 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.2

DANN

Benign

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000097

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.010

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