chr18-50267603-G-A

Variant names:

• chr18-50267603-G-A
• rs34500680
• ENST00000585672.5:c.1689C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001388147.1(MBD1):​c.1914C>T​(p.Ser638Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0579 in 1,533,968 control chromosomes in the GnomAD database, including 3,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.045 (226 hom., cov: 33)
  • Exomes 𝑓: 0.059 (2866 hom.)
• Consequence: MBD1 NM_001388147.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.29

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 (BayesDel_noAF=-0.84).
• BP6: Variant 18-50267603-G-A is Benign according to our data. Variant chr18-50267603-G-A is described in ClinVar as [Benign]. Clinvar id is 3056934.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD1	NM_001388147.1	c.1914C>T	p.Ser638Ser	synonymous_variant	Exon 17 of 17		NP_001375076.1
MBD1	NM_001399883.1	c.1911C>T	p.Ser637Ser	synonymous_variant	Exon 17 of 17		NP_001386812.1
MBD1	NM_001399889.1	c.1869C>T	p.Ser623Ser	synonymous_variant	Exon 17 of 17		NP_001386818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD1	ENST00000585672.5	c.1689C>T	p.Ser563Ser	synonymous_variant	Exon 15 of 15	1		ENSP00000466092.1
MBD1	ENST00000592060.5	c.1233C>T	p.Ser411Ser	synonymous_variant	Exon 11 of 11	1		ENSP00000467606.1
MBD1	ENST00000382948	c.*93C>T		3_prime_UTR_variant	Exon 17 of 17	2		ENSP00000372407.5

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6852 AN: 152144 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0423 AC: 5691 AN: 134632 Hom.: 199 AF XY: 0.0409 AC XY: 2995 AN XY: 73314

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0581

Gnomad EAS exome AF: 0.0000952

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0593 AC: 81915 AN: 1381708 Hom.: 2866 Cov.: 29 AF XY: 0.0580 AC XY: 39558 AN XY: 681920

Gnomad4 AFR exome AF: 0.00966

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.0661

Gnomad4 OTH exome AF: 0.0521

GnomAD4 genome AF: 0.0450 AC: 6847 AN: 152260 Hom.: 226 Cov.: 33 AF XY: 0.0464 AC XY: 3452 AN XY: 74436

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0356

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.0619

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0428 Hom.: 70

Bravo AF: 0.0381

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MBD1-related disorder Benign:1

Mar 20, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.42

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: rs34500680; hg19: chr18-47793973;