18-50273809-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015846.4(MBD1):c.1201C>G(p.Pro401Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,612 control chromosomes in the GnomAD database, including 32,536 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.18 (2606 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29930 hom.)
• Consequence: MBD1 NM_015846.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.120

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001339227).
• BP6: Variant 18-50273809-G-C is Benign according to our data. Variant chr18-50273809-G-C is described in ClinVar as [Benign]. Clinvar id is 3060114.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD1	NM_015846.4	c.1201C>G	p.Pro401Ala	missense_variant	12/17	ENST00000269468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD1	ENST00000269468.10	c.1201C>G	p.Pro401Ala	missense_variant	12/17	5	NM_015846.4

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27759 AN: 152044 Hom.: 2605 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.194 AC: 48490 AN: 250456 Hom.: 4862 AF XY: 0.195 AC XY: 26464 AN XY: 135532

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.187

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.201 AC: 294376 AN: 1461450 Hom.: 29930 Cov.: 34 AF XY: 0.202 AC XY: 146789 AN XY: 727042

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.183 AC: 27771 AN: 152162 Hom.: 2606 Cov.: 33 AF XY: 0.183 AC XY: 13634 AN XY: 74396

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.166

Alfa AF: 0.190 Hom.: 2262

Bravo AF: 0.176

TwinsUK AF: 0.205 AC: 761

ALSPAC AF: 0.206 AC: 792

ESP6500AA AF: 0.137 AC: 604

ESP6500EA AF: 0.197 AC: 1692

ExAC AF: 0.192 AC: 23299

Asia WGS AF: 0.220 AC: 765 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.192

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MBD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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	0.064
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.85	D;.;T;.;T;T;D;D;T;D;.;.;D;D;D;.;D;D
MetaRNN	Benign	0.0013	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.065	T;D;T;D;D;D;T;D;D;D;T;D;D;D;D;D;D;T
Polyphen		0.15, 0.36, 0.51, 0.64, 0.68, 0.43, 0.081	.;B;B;B;P;B;P;P;.;.;P;.;.;.;.;P;B;B
Vest4		0.13
MPC		0.49
ClinPred		0.0086	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.033
gMVP		0.74

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: rs125555; hg19: chr18-47800179; COSMIC: COSV99495569; COSMIC: COSV99495569;