3-129436571-A-G

Variant names:

• chr3-129436571-A-G
• rs2307298
• NM_001276270.2:c.1073T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001276270.2(MBD4):​c.1073T>C​(p.Ile358Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,030 control chromosomes in the GnomAD database, including 84 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I358V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 32)
  • Exomes 𝑓: 0.010 (77 hom.)
• Consequence: MBD4 NM_001276270.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0510
• Publications: 13 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002847582).
• BP6: Variant 3-129436571-A-G is Benign according to our data. Variant chr3-129436571-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1299953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00705 (1073/152204) while in subpopulation NFE AF = 0.0113 (767/68008). AF 95% confidence interval is 0.0106. There are 7 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276270.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	NM_001276270.2	MANE Select	c.1073T>C	p.Ile358Thr	missense	Exon 3 of 8	NP_001263199.1
	MBD4	NM_003925.3		c.1073T>C	p.Ile358Thr	missense	Exon 3 of 8	NP_003916.1
	MBD4	NM_001276271.2		c.1073T>C	p.Ile358Thr	missense	Exon 3 of 7	NP_001263200.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	ENST00000429544.7	TSL:1 MANE Select	c.1073T>C	p.Ile358Thr	missense	Exon 3 of 8	ENSP00000394080.2
	MBD4	ENST00000249910.5	TSL:1	c.1073T>C	p.Ile358Thr	missense	Exon 3 of 8	ENSP00000249910.1
	MBD4	ENST00000503197.5	TSL:1	c.1073T>C	p.Ile358Thr	missense	Exon 3 of 8	ENSP00000424873.1

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1075 AN: 152086 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00744 AC: 1869 AN: 251328 AF XY: 0.00762

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0105 AC: 15292 AN: 1461826 Hom.: 77 Cov.: 33 AF XY: 0.0103 AC XY: 7481 AN XY: 727216

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00724 AC: 324 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00926 AC: 242 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00285 AC: 246 AN: 86256

European-Finnish (FIN) AF: 0.00320 AC: 171 AN: 53414

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0122 AC: 13537 AN: 1111978

Other (OTH) AF: 0.0105 AC: 637 AN: 60392

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152204 Hom.: 7 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74424

African (AFR) AF: 0.00210 AC: 87 AN: 41522

American (AMR) AF: 0.00889 AC: 136 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 767 AN: 68008

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0105 Hom.: 30

Bravo AF: 0.00764

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0117 AC: 101

ExAC AF: 0.00695 AC: 844

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBD4: BS1, BS2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

May 14, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

MBD4-related disorder Benign:1

Feb 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Inborn genetic diseases Benign:1

Oct 29, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.8
DANN	Benign	0.43
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.051
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.22
Sift	Benign	0.34	T
Sift4G	Benign	0.91	T
Polyphen		0.0010	B
Vest4		0.069
MVP		0.63
MPC		0.12
ClinPred		0.0010	T
GERP RS		-1.9
Varity_R		0.064
gMVP		0.059
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2307298; hg19: chr3-129155414;