3-129433387-C-A

Variant names:

• chr3-129433387-C-A
• rs3138355
• NM_001276270.2:c.1394-140G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001276270.2(MBD4):​c.1394-140G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.232
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	NM_001276270.2	MANE Select	c.1394-140G>T		intron	N/A	NP_001263199.1	O95243-2
	MBD4	NM_003925.3		c.1412-140G>T		intron	N/A	NP_003916.1	O95243-1
	MBD4	NM_001276271.2		c.1412-140G>T		intron	N/A	NP_001263200.1	O95243-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	ENST00000429544.7	TSL:1 MANE Select	c.1394-140G>T		intron	N/A	ENSP00000394080.2	O95243-2
	MBD4	ENST00000249910.5	TSL:1	c.1412-140G>T		intron	N/A	ENSP00000249910.1	O95243-1
	MBD4	ENST00000503197.5	TSL:1	c.1412-140G>T		intron	N/A	ENSP00000424873.1	O95243-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 744046 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 388264

African (AFR) AF: 0.00 AC: 0 AN: 17174

American (AMR) AF: 0.00 AC: 0 AN: 27316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19826

East Asian (EAS) AF: 0.00 AC: 0 AN: 32798

South Asian (SAS) AF: 0.00 AC: 0 AN: 59736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 513066

Other (OTH) AF: 0.00 AC: 0 AN: 36244

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.3
DANN	Benign	0.72
PhyloP100		0.23

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: rs3138355; hg19: chr3-129152230;