rs3138341

Variant names:

• chr3-129436393-A-C
• rs3138341
• NM_001276270.2:c.1183+68T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001276270.2(MBD4):​c.1183+68T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,592,636 control chromosomes in the GnomAD database, including 86 homozygotes. 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: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (48 hom.)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2028/152332) while in subpopulation AFR AF = 0.0437 (1818/41560). AF 95% confidence interval is 0.0421. There are 38 homozygotes in GnomAd4. There are 962 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 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.1183+68T>G		intron	N/A	NP_001263199.1
	MBD4	NM_003925.3		c.1201+50T>G		intron	N/A	NP_003916.1
	MBD4	NM_001276271.2		c.1201+50T>G		intron	N/A	NP_001263200.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	ENST00000429544.7	TSL:1 MANE Select	c.1183+68T>G		intron	N/A	ENSP00000394080.2
	MBD4	ENST00000249910.5	TSL:1	c.1201+50T>G		intron	N/A	ENSP00000249910.1
	MBD4	ENST00000503197.5	TSL:1	c.1201+50T>G		intron	N/A	ENSP00000424873.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2017 AN: 152214 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00378 AC: 927 AN: 245500 AF XY: 0.00326

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00173 AC: 2491 AN: 1440304 Hom.: 48 Cov.: 28 AF XY: 0.00157 AC XY: 1127 AN XY: 716372

African (AFR) AF: 0.0486 AC: 1609 AN: 33120

American (AMR) AF: 0.00423 AC: 187 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 44 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48476

Middle Eastern (MID) AF: 0.00489 AC: 28 AN: 5726

European-Non Finnish (NFE) AF: 0.000303 AC: 333 AN: 1097962

Other (OTH) AF: 0.00465 AC: 278 AN: 59736

GnomAD4 genome AF: 0.0133 AC: 2028 AN: 152332 Hom.: 38 Cov.: 32 AF XY: 0.0129 AC XY: 962 AN XY: 74492

African (AFR) AF: 0.0437 AC: 1818 AN: 41560

American (AMR) AF: 0.00921 AC: 141 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68028

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00530 Hom.: 14

Bravo AF: 0.0158

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.48
PhyloP100		0.078
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: rs3138341; hg19: chr3-129155236;