18-50274051-A-G

Variant names:

• chr18-50274051-A-G
• rs140689
• NM_015846.4:c.1146+135T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015846.4(MBD1):​c.1146+135T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000809 in 1,236,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: MBD1 NM_015846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

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.1146+135T>C		intron	N/A	NP_056671.2
	MBD1	NM_001323942.2		c.1221+135T>C		intron	N/A	NP_001310871.1
	MBD1	NM_001323947.2		c.1221+135T>C		intron	N/A	NP_001310876.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	ENST00000269468.10	TSL:5 MANE Select	c.1146+135T>C		intron	N/A	ENSP00000269468.5
	MBD1	ENST00000590208.5	TSL:1	c.1146+135T>C		intron	N/A	ENSP00000468785.1
	MBD1	ENST00000588937.5	TSL:1	c.1077+135T>C		intron	N/A	ENSP00000467763.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.09e-7 AC: 1 AN: 1236442 Hom.: 0 AF XY: 0.00000160 AC XY: 1 AN XY: 625080

African (AFR) AF: 0.00 AC: 0 AN: 29238

American (AMR) AF: 0.00 AC: 0 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24642

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38630

South Asian (SAS) AF: 0.00 AC: 0 AN: 81292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 918924

Other (OTH) AF: 0.00 AC: 0 AN: 53238

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs140689; hg19: chr18-47800421;