rs140693

Positions:

• chr3-129436608-C-T

Variant summary

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

The ENST00000429544.7(MBD4):​c.1036G>A​(p.Glu346Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,056 control chromosomes in the GnomAD database, including 4,120 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. Synonymous variant affecting the same amino acid position (i.e. E346E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (602 hom., cov: 32)
  • Exomes 𝑓: 0.020 (3518 hom.)
• Consequence: MBD4 ENST00000429544.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.75

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=0.0010472536).
• BP6: Variant 3-129436608-C-T is Benign according to our data. Variant chr3-129436608-C-T is described in ClinVar as [Benign]. Clinvar id is 1266648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD4	NM_001276270.2	c.1036G>A	p.Glu346Lys	missense_variant	3/8	ENST00000429544.7	NP_001263199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD4	ENST00000429544.7	c.1036G>A	p.Glu346Lys	missense_variant	3/8	1	NM_001276270.2	ENSP00000394080	A2

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5423 AN: 152114 Hom.: 601 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.0353

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0583 AC: 14650 AN: 251334 Hom.: 2045 AF XY: 0.0508 AC XY: 6907 AN XY: 135850

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.408

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0200 AC: 29184 AN: 1461824 Hom.: 3518 Cov.: 33 AF XY: 0.0193 AC XY: 14039 AN XY: 727214

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.00463

Gnomad4 EAS exome AF: 0.369

Gnomad4 SAS exome AF: 0.0243

Gnomad4 FIN exome AF: 0.00382

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0357 AC: 5437 AN: 152232 Hom.: 602 Cov.: 32 AF XY: 0.0410 AC XY: 3050 AN XY: 74432

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.0351

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0176 Hom.: 705

Bravo AF: 0.0454

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.0509 AC: 6183

Asia WGS AF: 0.173 AC: 600 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00385

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 16803845, 19469655, 18495292, 23027038) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.0020
DANN	Benign	0.77
DEOGEN2	Benign	0.090	.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.47	T;T;T;T
MetaRNN	Benign	0.0010	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.94	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.41	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.0060	B;B;B;.
Vest4		0.092
MPC		0.11
ClinPred		0.0022	T
GERP RS		-3.7
Varity_R		0.064
gMVP		0.11

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: rs140693; hg19: chr3-129155451; COSMIC: COSV51444514; COSMIC: COSV51444514;