3-129431542-C-G

Variant summary

Our verdict is Benign. Variant got -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:1 B:3
• Conservation: PhyloP100: 1.40

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 -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 id is 218624.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD4	NM_001276270.2	c.1684G>C	p.Asp562His	missense_variant	8/8	ENST00000429544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD4	ENST00000429544.7	c.1684G>C	p.Asp562His	missense_variant	8/8	1	NM_001276270.2	A2

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

GnomAD3 exomes AF: 0.00530 AC: 1331 AN: 251134 Hom.: 12 AF XY: 0.00583 AC XY: 792 AN XY: 135746

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 SAS exome AF: 0.00970

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

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.00827

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.000492

Gnomad4 NFE exome AF: 0.00800

Gnomad4 OTH exome AF: 0.00779

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

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00782

Gnomad4 OTH AF: 0.00851

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 17, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MBD4: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		1.0	D;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

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: rs2307293; hg19: chr3-129150385; COSMIC: COSV51445373; COSMIC: COSV51445373;