18-50270029-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000339998.10(MBD1):c.1635T>G(p.Ile545Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,598,022 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (68 hom.)
• Consequence: MBD1 ENST00000339998.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.712

Genes affected

MBD1 (HGNC:6916): (methyl-CpG binding domain protein 1) 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 multiple domains: MBD at the N-terminus that functions both in binding to methylated DNA and in protein interactions; several CXXC-type zinc finger domains that mediate binding to non-methylated CpG dinucleotides; transcriptional repression domain (TRD) at the C-terminus that is involved in transcription repression and in protein interactions. Numerous alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028661191).
• BP6: Variant 18-50270029-A-C is Benign according to our data. Variant chr18-50270029-A-C is described in ClinVar as [Benign]. Clinvar id is 3024799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD1	NM_015846.4	c.*33-211T>G		intron_variant		ENST00000269468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD1	ENST00000269468.10	c.*33-211T>G		intron_variant		5	NM_015846.4

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 980 AN: 152168 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00970

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00791 AC: 1823 AN: 230376 Hom.: 13 AF XY: 0.00856 AC XY: 1089 AN XY: 127186

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00612

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00856 AC: 12375 AN: 1445736 Hom.: 68 Cov.: 30 AF XY: 0.00869 AC XY: 6251 AN XY: 719634

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.00664

Gnomad4 NFE exome AF: 0.00910

Gnomad4 OTH exome AF: 0.00737

GnomAD4 genome AF: 0.00644 AC: 980 AN: 152286 Hom.: 4 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74462

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.00970

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00954 Hom.: 3

Bravo AF: 0.00573

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00114 AC: 2

ESP6500EA AF: 0.00779 AC: 31

ExAC AF: 0.00780 AC: 914

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00998

EpiControl AF: 0.0101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MBD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

MBD1: PP3, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	3.4
Dann	Benign	0.87
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0029	T
MetaSVM	Uncertain	-0.076	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.10	B
Vest4		0.19
MVP		0.33
ClinPred		0.011	T
GERP RS		1.4

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: rs183864846; hg19: chr18-47796399;