rs2307289

Positions:

• chr3-129436620-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001276270.2(MBD4):​c.1024T>C​(p.Ser342Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,052 control chromosomes in the GnomAD database, including 1,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (380 hom., cov: 32)
  • Exomes 𝑓: 0.012 (914 hom.)
• Consequence: MBD4 NM_001276270.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.217

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016411841).
• BP6: Variant 3-129436620-A-G is Benign according to our data. Variant chr3-129436620-A-G is described in ClinVar as [Benign]. Clinvar id is 1268570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD4	NM_001276270.2	c.1024T>C	p.Ser342Pro	missense_variant	3/8	ENST00000429544.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD4	ENST00000429544.7	c.1024T>C	p.Ser342Pro	missense_variant	3/8	1	NM_001276270.2	A2

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6198 AN: 152116 Hom.: 380 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0243 AC: 6104 AN: 251338 Hom.: 341 AF XY: 0.0261 AC XY: 3547 AN XY: 135860

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0155

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0119 AC: 17452 AN: 1461818 Hom.: 914 Cov.: 33 AF XY: 0.0142 AC XY: 10313 AN XY: 727208

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0150

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.0168

GnomAD4 genome AF: 0.0408 AC: 6206 AN: 152234 Hom.: 380 Cov.: 32 AF XY: 0.0408 AC XY: 3041 AN XY: 74448

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00213

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0145 Hom.: 153

Bravo AF: 0.0433

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.123 AC: 542

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.0285 AC: 3465

Asia WGS AF: 0.0800 AC: 277 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

MBD4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.90
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.41	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.34	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.048
MPC		0.13
ClinPred		0.0030	T
GERP RS		2.7
Varity_R		0.20
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2307289; hg19: chr3-129155463; COSMIC: COSV105073110; COSMIC: COSV105073110;