rs3138340

Variant names:

• chr3-129437354-G-C
• rs3138340
• NM_001276270.2:c.336-46C>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.336-46C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,476,176 control chromosomes in the GnomAD database, including 90 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 0.014 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (49 hom.)
• Consequence: MBD4 NM_001276270.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443
• 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=-0.73).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2095/152248) while in subpopulation AFR AF = 0.0452 (1878/41542). AF 95% confidence interval is 0.0435. There are 41 homozygotes in GnomAd4. There are 999 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.336-46C>G		intron	N/A	NP_001263199.1
	MBD4	NM_003925.3		c.336-46C>G		intron	N/A	NP_003916.1
	MBD4	NM_001276271.2		c.336-46C>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.336-46C>G		intron	N/A	ENSP00000394080.2
	MBD4	ENST00000249910.5	TSL:1	c.336-46C>G		intron	N/A	ENSP00000249910.1
	MBD4	ENST00000503197.5	TSL:1	c.336-46C>G		intron	N/A	ENSP00000424873.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 152130 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

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: 0.000500

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00393 AC: 896 AN: 228118 AF XY: 0.00343

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00179 AC: 2372 AN: 1323928 Hom.: 49 Cov.: 20 AF XY: 0.00162 AC XY: 1073 AN XY: 664262

African (AFR) AF: 0.0500 AC: 1545 AN: 30918

American (AMR) AF: 0.00428 AC: 187 AN: 43646

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 43 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 39068

South Asian (SAS) AF: 0.000148 AC: 12 AN: 81054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39372

Middle Eastern (MID) AF: 0.00447 AC: 19 AN: 4252

European-Non Finnish (NFE) AF: 0.000304 AC: 305 AN: 1004214

Other (OTH) AF: 0.00465 AC: 261 AN: 56082

GnomAD4 genome AF: 0.0138 AC: 2095 AN: 152248 Hom.: 41 Cov.: 33 AF XY: 0.0134 AC XY: 999 AN XY: 74460

African (AFR) AF: 0.0452 AC: 1878 AN: 41542

American (AMR) AF: 0.00942 AC: 144 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68014

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00782 Hom.: 4

Bravo AF: 0.0162

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	-0.73
CADD	Benign	8.2
DANN	Benign	0.76
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3138340; hg19: chr3-129156197;