rs183864846

Variant names:

• chr18-50270029-A-C
• rs183864846
• ENST00000339998.10:c.1635T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001204142.2(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. 14/17 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 NM_001204142.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.712
• Publications: 7 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 -10 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 VariationId is 3024799.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204142.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	NM_015846.4	MANE Select	c.*33-211T>G		intron	N/A	NP_056671.2
	MBD1	NM_001204142.2		c.1635T>G	p.Ile545Met	missense	Exon 14 of 14	NP_001191071.1	Q9UIS9-6
	MBD1	NM_001204137.2		c.*1472T>G		3_prime_UTR	Exon 17 of 17	NP_001191066.1	Q9UIS9-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	ENST00000339998.10	TSL:1	c.1635T>G	p.Ile545Met	missense	Exon 14 of 14	ENSP00000339546.5	Q9UIS9-6
	MBD1	ENST00000269468.10	TSL:5 MANE Select	c.*33-211T>G		intron	N/A	ENSP00000269468.5	Q9UIS9-1
	MBD1	ENST00000590208.5	TSL:1	c.1779-211T>G		intron	N/A	ENSP00000468785.1	Q9UIS9-12

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

GnomAD2 exomes AF: 0.00791 AC: 1823 AN: 230376 AF XY: 0.00856

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 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

African (AFR) AF: 0.00155 AC: 52 AN: 33466

American (AMR) AF: 0.00235 AC: 105 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 426 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0103 AC: 889 AN: 86244

European-Finnish (FIN) AF: 0.00664 AC: 253 AN: 38098

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5756

European-Non Finnish (NFE) AF: 0.00910 AC: 10118 AN: 1111354

Other (OTH) AF: 0.00737 AC: 444 AN: 60272

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

African (AFR) AF: 0.00176 AC: 73 AN: 41538

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00970 AC: 660 AN: 68030

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00883 Hom.: 4

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MBD1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
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
PhyloP100		-0.71
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
Mutation Taster		=99/1	polymorphism

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: rs183864846; hg19: chr18-47796399; COSMIC: COSV106091641; COSMIC: COSV106091641;