3-129436827-C-T

Variant names:

• chr3-129436827-C-T
• rs10342
• NM_001276270.2:c.817G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001276270.2(MBD4):​c.817G>A​(p.Ala273Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 1,614,010 control chromosomes in the GnomAD database, including 6,177 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A273A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.077 (507 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5670 hom.)
• Consequence: MBD4 NM_001276270.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.275
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015313923).
• BP6: Variant 3-129436827-C-T is Benign according to our data. Variant chr3-129436827-C-T is described in ClinVar as Benign. ClinVar VariationId is 1236752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

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.817G>A	p.Ala273Thr	missense	Exon 3 of 8	NP_001263199.1	O95243-2
	MBD4	NM_003925.3		c.817G>A	p.Ala273Thr	missense	Exon 3 of 8	NP_003916.1	O95243-1
	MBD4	NM_001276271.2		c.817G>A	p.Ala273Thr	missense	Exon 3 of 7	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.817G>A	p.Ala273Thr	missense	Exon 3 of 8	ENSP00000394080.2	O95243-2
	MBD4	ENST00000249910.5	TSL:1	c.817G>A	p.Ala273Thr	missense	Exon 3 of 8	ENSP00000249910.1	O95243-1
	MBD4	ENST00000503197.5	TSL:1	c.817G>A	p.Ala273Thr	missense	Exon 3 of 8	ENSP00000424873.1	O95243-3

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11681 AN: 152144 Hom.: 504 Cov.: 32

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0770

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0381

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0947

GnomAD2 exomes AF: 0.0801 AC: 20148 AN: 251388 AF XY: 0.0839

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.0562

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0613

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.0841

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0848 AC: 124002 AN: 1461748 Hom.: 5670 Cov.: 34 AF XY: 0.0865 AC XY: 62928 AN XY: 727188

African (AFR) AF: 0.0686 AC: 2297 AN: 33480

American (AMR) AF: 0.0584 AC: 2612 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4263 AN: 26134

East Asian (EAS) AF: 0.0493 AC: 1959 AN: 39698

South Asian (SAS) AF: 0.112 AC: 9658 AN: 86256

European-Finnish (FIN) AF: 0.0389 AC: 2078 AN: 53360

Middle Eastern (MID) AF: 0.126 AC: 727 AN: 5768

European-Non Finnish (NFE) AF: 0.0853 AC: 94807 AN: 1111934

Other (OTH) AF: 0.0927 AC: 5601 AN: 60394

GnomAD4 genome AF: 0.0768 AC: 11693 AN: 152262 Hom.: 507 Cov.: 32 AF XY: 0.0761 AC XY: 5661 AN XY: 74436

African (AFR) AF: 0.0674 AC: 2801 AN: 41552

American (AMR) AF: 0.0769 AC: 1176 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3472

East Asian (EAS) AF: 0.0616 AC: 319 AN: 5182

South Asian (SAS) AF: 0.104 AC: 499 AN: 4820

European-Finnish (FIN) AF: 0.0381 AC: 404 AN: 10602

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0835 AC: 5680 AN: 68020

Other (OTH) AF: 0.0961 AC: 203 AN: 2112

Alfa AF: 0.0631 Hom.: 1610

Bravo AF: 0.0792

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0771 AC: 297

ESP6500AA AF: 0.0667 AC: 294

ESP6500EA AF: 0.0885 AC: 761

ExAC AF: 0.0810 AC: 9840

Asia WGS AF: 0.0990 AC: 347 AN: 3478

EpiCase AF: 0.0949

EpiControl AF: 0.0978

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.28
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.21
Sift	Benign	0.30	T
Sift4G	Benign	0.68	T
Polyphen		0.041	B
Vest4		0.011
MPC		0.097
ClinPred		0.0012	T
GERP RS		-0.94
Varity_R		0.093
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs10342; hg19: chr3-129155670; COSMIC: COSV51444644; COSMIC: COSV51444644;