18-50273600-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015846.4(MBD1):c.1410G>A(p.Pro470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,613,006 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: MBD1 NM_015846.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 18-50273600-C-T is Benign according to our data. Variant chr18-50273600-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 403072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD1	NM_015846.4	c.1410G>A	p.Pro470=	synonymous_variant	12/17	ENST00000269468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD1	ENST00000269468.10	c.1410G>A	p.Pro470=	synonymous_variant	12/17	5	NM_015846.4

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00307 AC: 767 AN: 249934 Hom.: 5 AF XY: 0.00307 AC XY: 415 AN XY: 135220

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00365 AC: 5337 AN: 1460680 Hom.: 16 Cov.: 31 AF XY: 0.00360 AC XY: 2619 AN XY: 726660

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00582

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00767

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00249 AC: 380 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74484

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00374 Hom.: 0

Bravo AF: 0.00210

EpiCase AF: 0.00354

EpiControl AF: 0.00433

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 39/13006=0.2% -

MBD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.64
Cadd	Benign	2.6
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs116701586; hg19: chr18-47799970;