NM_015846.4:c.1201C>G

Variant names:

• chr18-50273809-G-C
• rs125555
• NM_015846.4:c.1201C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.18 (2606 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29930 hom.)
• Consequence: MBD1 NM_015846.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.120
• Publications: 45 publications found

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

Our verdict: Benign. The variant received -13 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 VariationId is 3060114.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	NM_015846.4	MANE Select	c.1201C>G	p.Pro401Ala	missense	Exon 12 of 17	NP_056671.2
	MBD1	NM_001323942.2		c.1276C>G	p.Pro426Ala	missense	Exon 13 of 17	NP_001310871.1
	MBD1	NM_001323947.2		c.1276C>G	p.Pro426Ala	missense	Exon 13 of 17	NP_001310876.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	ENST00000269468.10	TSL:5 MANE Select	c.1201C>G	p.Pro401Ala	missense	Exon 12 of 17	ENSP00000269468.5
	MBD1	ENST00000590208.5	TSL:1	c.1201C>G	p.Pro401Ala	missense	Exon 12 of 16	ENSP00000468785.1
	MBD1	ENST00000588937.5	TSL:1	c.1132C>G	p.Pro378Ala	missense	Exon 10 of 13	ENSP00000467763.1

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

GnomAD2 exomes AF: 0.194 AC: 48490 AN: 250456 AF XY: 0.195

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 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

African (AFR) AF: 0.137 AC: 4592 AN: 33480

American (AMR) AF: 0.176 AC: 7886 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 5172 AN: 26136

East Asian (EAS) AF: 0.184 AC: 7320 AN: 39700

South Asian (SAS) AF: 0.207 AC: 17858 AN: 86254

European-Finnish (FIN) AF: 0.194 AC: 10273 AN: 52996

Middle Eastern (MID) AF: 0.181 AC: 1046 AN: 5768

European-Non Finnish (NFE) AF: 0.205 AC: 228076 AN: 1112002

Other (OTH) AF: 0.201 AC: 12153 AN: 60390

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

African (AFR) AF: 0.140 AC: 5805 AN: 41508

American (AMR) AF: 0.170 AC: 2595 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3470

East Asian (EAS) AF: 0.186 AC: 960 AN: 5168

South Asian (SAS) AF: 0.213 AC: 1028 AN: 4820

European-Finnish (FIN) AF: 0.196 AC: 2083 AN: 10602

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14054 AN: 67976

Other (OTH) AF: 0.166 AC: 351 AN: 2114

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: no assertion criteria provided

Submissions by phenotype

MBD1-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.12
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.19
Sift	Uncertain	0.018	D
Sift4G	Benign	0.065	T
Polyphen		0.15	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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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