3-129431542-C-G

Variant names:

• chr3-129431542-C-G
• rs2307293
• NM_001276270.2:c.1684G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001276270.2(MBD4):​c.1684G>C​(p.Asp562His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,613,132 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D562D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (68 hom.)
• Consequence: MBD4 NM_001276270.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.40
• Publications: 26 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009672582).
• BP6: Variant 3-129431542-C-G is Benign according to our data. Variant chr3-129431542-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218624.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00525 (799/152302) while in subpopulation SAS AF = 0.0118 (57/4828). AF 95% confidence interval is 0.00936. There are 3 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	NM_001276270.2	MANE Select	c.1684G>C	p.Asp562His	missense	Exon 8 of 8	NP_001263199.1	O95243-2
	MBD4	NM_003925.3		c.1702G>C	p.Asp568His	missense	Exon 8 of 8	NP_003916.1	O95243-1
	MBD4	NM_001276273.2		c.748G>C	p.Asp250His	missense	Exon 7 of 7	NP_001263202.1	O95243-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD4	ENST00000429544.7	TSL:1 MANE Select	c.1684G>C	p.Asp562His	missense	Exon 8 of 8	ENSP00000394080.2	O95243-2
	MBD4	ENST00000249910.5	TSL:1	c.1702G>C	p.Asp568His	missense	Exon 8 of 8	ENSP00000249910.1	O95243-1
	MBD4	ENST00000393278.6	TSL:1	c.748G>C	p.Asp250His	missense	Exon 7 of 7	ENSP00000376959.2	O95243-6

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 800 AN: 152184 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00530 AC: 1331 AN: 251134 AF XY: 0.00583

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00668

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00739 AC: 10789 AN: 1460830 Hom.: 68 Cov.: 30 AF XY: 0.00757 AC XY: 5501 AN XY: 726772

African (AFR) AF: 0.00134 AC: 45 AN: 33470

American (AMR) AF: 0.00340 AC: 152 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00827 AC: 216 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.0110 AC: 948 AN: 86224

European-Finnish (FIN) AF: 0.000492 AC: 26 AN: 52874

Middle Eastern (MID) AF: 0.00684 AC: 39 AN: 5700

European-Non Finnish (NFE) AF: 0.00800 AC: 8892 AN: 1111690

Other (OTH) AF: 0.00779 AC: 470 AN: 60356

GnomAD4 genome AF: 0.00525 AC: 799 AN: 152302 Hom.: 3 Cov.: 33 AF XY: 0.00487 AC XY: 363 AN XY: 74476

African (AFR) AF: 0.00111 AC: 46 AN: 41552

American (AMR) AF: 0.00483 AC: 74 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00782 AC: 532 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00695 Hom.: 4

Bravo AF: 0.00551

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00539 AC: 654

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.46
MPC		0.55
ClinPred		0.016	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.73
Mutation Taster		=92/8	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: rs2307293; hg19: chr3-129150385; COSMIC: COSV51445373; COSMIC: COSV51445373;