18-50273657-C-T

Variant names:

• chr18-50273657-C-T
• rs139622890
• NM_015846.4:c.1353G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015846.4(MBD1):​c.1353G>A​(p.Pro451Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,980 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: MBD1 NM_015846.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.771
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-50273657-C-T is Benign according to our data. Variant chr18-50273657-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 783070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.771 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	NM_015846.4	MANE Select	c.1353G>A	p.Pro451Pro	synonymous	Exon 12 of 17	NP_056671.2
	MBD1	NM_001323942.2		c.1428G>A	p.Pro476Pro	synonymous	Exon 13 of 17	NP_001310871.1	A0A994J7H0
	MBD1	NM_001323947.2		c.1428G>A	p.Pro476Pro	synonymous	Exon 13 of 17	NP_001310876.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	ENST00000269468.10	TSL:5 MANE Select	c.1353G>A	p.Pro451Pro	synonymous	Exon 12 of 17	ENSP00000269468.5	Q9UIS9-1
	MBD1	ENST00000590208.5	TSL:1	c.1353G>A	p.Pro451Pro	synonymous	Exon 12 of 16	ENSP00000468785.1	Q9UIS9-12
	MBD1	ENST00000588937.5	TSL:1	c.1284G>A	p.Pro428Pro	synonymous	Exon 10 of 13	ENSP00000467763.1	Q9UIS9-2

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000693 AC: 174 AN: 251060 AF XY: 0.000700

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00141

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00133 AC: 1940 AN: 1461640 Hom.: 4 Cov.: 31 AF XY: 0.00129 AC XY: 936 AN XY: 727096

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00190 AC: 101 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00158 AC: 1756 AN: 1112004

Other (OTH) AF: 0.00108 AC: 65 AN: 60396

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74492

African (AFR) AF: 0.000240 AC: 10 AN: 41586

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000657

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MBD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.64
PhyloP100		-0.77
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139622890; hg19: chr18-47800027; COSMIC: COSV54004063; COSMIC: COSV54004063;