rs3138360

Positions:

• chr3-129432327-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001276270.2(MBD4):​c.1647+176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,509,652 control chromosomes in the GnomAD database, including 2,144 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 0.039 (165 hom., cov: 32)
  • Exomes 𝑓: 0.051 (1979 hom.)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD4	NM_001276270.2	c.1647+176G>A		intron_variant		ENST00000429544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD4	ENST00000429544.7	c.1647+176G>A		intron_variant		1	NM_001276270.2	A2

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5869 AN: 152078 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.0779

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0536

Gnomad OTH AF: 0.0465

GnomAD4 exome AF: 0.0510 AC: 69289 AN: 1357456 Hom.: 1979 Cov.: 31 AF XY: 0.0525 AC XY: 35024 AN XY: 666736

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0987

Gnomad4 EAS exome AF: 0.0177

Gnomad4 SAS exome AF: 0.0794

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.0535

GnomAD4 genome AF: 0.0386 AC: 5875 AN: 152196 Hom.: 165 Cov.: 32 AF XY: 0.0383 AC XY: 2848 AN XY: 74398

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.0788

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.0465

Alfa AF: 0.0434 Hom.: 33

Bravo AF: 0.0376

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs3138360; hg19: chr3-129151170;