rs3138360

Variant names:

• chr3-129432327-C-T
• rs3138360
• NM_001276270.2:c.1647+176G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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=-0.87).
• 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 rank	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.1647+176G>A		intron_variant	Intron 7 of 7	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.1647+176G>A		intron_variant	Intron 7 of 7	1	NM_001276270.2	ENSP00000394080.2

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

African (AFR) AF: 0.0108 AC: 336 AN: 31124

American (AMR) AF: 0.0247 AC: 851 AN: 34446

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 2312 AN: 23420

East Asian (EAS) AF: 0.0177 AC: 627 AN: 35512

South Asian (SAS) AF: 0.0794 AC: 5879 AN: 74026

European-Finnish (FIN) AF: 0.0240 AC: 790 AN: 32978

Middle Eastern (MID) AF: 0.102 AC: 404 AN: 3956

European-Non Finnish (NFE) AF: 0.0517 AC: 55055 AN: 1065274

Other (OTH) AF: 0.0535 AC: 3035 AN: 56720

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

African (AFR) AF: 0.0113 AC: 471 AN: 41528

American (AMR) AF: 0.0310 AC: 474 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 362 AN: 3470

East Asian (EAS) AF: 0.0185 AC: 96 AN: 5176

South Asian (SAS) AF: 0.0788 AC: 380 AN: 4824

European-Finnish (FIN) AF: 0.0233 AC: 247 AN: 10598

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0537 AC: 3649 AN: 68002

Other (OTH) AF: 0.0465 AC: 98 AN: 2108

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
PhyloP100		-1.8
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: rs3138360; hg19: chr3-129151170;