chr3-129433246-G-A

Variant names:

• chr3-129433246-G-A
• rs140696
• NM_001276270.2:c.1395C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Publications: 20 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 -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 VariationId 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.

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.1395C>T	p.Gly465Gly	splice_region synonymous	Exon 6 of 8	NP_001263199.1
	MBD4	NM_003925.3		c.1413C>T	p.Gly471Gly	splice_region synonymous	Exon 6 of 8	NP_003916.1
	MBD4	NM_001276271.2		c.1413C>T	p.Gly471Gly	splice_region synonymous	Exon 6 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.1395C>T	p.Gly465Gly	splice_region synonymous	Exon 6 of 8	ENSP00000394080.2
	MBD4	ENST00000249910.5	TSL:1	c.1413C>T	p.Gly471Gly	splice_region synonymous	Exon 6 of 8	ENSP00000249910.1
	MBD4	ENST00000503197.5	TSL:1	c.1413C>T	p.Gly471Gly	splice_region synonymous	Exon 6 of 8	ENSP00000424873.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20023 AN: 152024 Hom.: 1672 Cov.: 33

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

GnomAD2 exomes AF: 0.116 AC: 29233 AN: 251420 AF XY: 0.123

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: 157976 AN: 1461310 Hom.: 10307 Cov.: 33 AF XY: 0.113 AC XY: 81881 AN XY: 726970

African (AFR) AF: 0.225 AC: 7542 AN: 33458

American (AMR) AF: 0.0736 AC: 3293 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4379 AN: 26128

East Asian (EAS) AF: 0.0646 AC: 2564 AN: 39692

South Asian (SAS) AF: 0.246 AC: 21225 AN: 86234

European-Finnish (FIN) AF: 0.0417 AC: 2229 AN: 53408

Middle Eastern (MID) AF: 0.159 AC: 917 AN: 5768

European-Non Finnish (NFE) AF: 0.0976 AC: 108492 AN: 1111522

Other (OTH) AF: 0.121 AC: 7335 AN: 60376

GnomAD4 genome AF: 0.132 AC: 20052 AN: 152142 Hom.: 1677 Cov.: 33 AF XY: 0.131 AC XY: 9777 AN XY: 74374

African (AFR) AF: 0.217 AC: 9001 AN: 41492

American (AMR) AF: 0.106 AC: 1620 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3470

East Asian (EAS) AF: 0.0808 AC: 419 AN: 5184

South Asian (SAS) AF: 0.240 AC: 1159 AN: 4822

European-Finnish (FIN) AF: 0.0397 AC: 419 AN: 10562

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0945 AC: 6425 AN: 68000

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.109 Hom.: 3637

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

Submissions by phenotype

not provided Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 04, 2021

GeneDx

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.2
DANN	Benign	0.95
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs140696; hg19: chr3-129152089; COSMIC: COSV51444636; COSMIC: COSV51444636;