18-50274051-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015846.4(MBD1):​c.1146+135T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,386,462 control chromosomes in the GnomAD database, including 89,811 homozygotes. 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: 𝑓 0.29 (7322 hom., cov: 32)
  • Exomes 𝑓: 0.36 (82489 hom.)
• Consequence: MBD1 NM_015846.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.400
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.375 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	NM_015846.4	MANE Select	c.1146+135T>A		intron	N/A	NP_056671.2
	MBD1	NM_001323942.2		c.1221+135T>A		intron	N/A	NP_001310871.1	A0A994J7H0
	MBD1	NM_001323947.2		c.1221+135T>A		intron	N/A	NP_001310876.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD1	ENST00000269468.10	TSL:5 MANE Select	c.1146+135T>A		intron	N/A	ENSP00000269468.5	Q9UIS9-1
	MBD1	ENST00000590208.5	TSL:1	c.1146+135T>A		intron	N/A	ENSP00000468785.1	Q9UIS9-12
	MBD1	ENST00000588937.5	TSL:1	c.1077+135T>A		intron	N/A	ENSP00000467763.1	Q9UIS9-2

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44352 AN: 151944 Hom.: 7322 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.429

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.320

GnomAD4 exome AF: 0.355 AC: 438663 AN: 1234400 Hom.: 82489 AF XY: 0.355 AC XY: 221543 AN XY: 624106

African (AFR) AF: 0.132 AC: 3856 AN: 29222

American (AMR) AF: 0.213 AC: 9394 AN: 44178

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 8100 AN: 24628

East Asian (EAS) AF: 0.0869 AC: 3355 AN: 38626

South Asian (SAS) AF: 0.289 AC: 23491 AN: 81254

European-Finnish (FIN) AF: 0.410 AC: 17293 AN: 42132

Middle Eastern (MID) AF: 0.332 AC: 1370 AN: 4130

European-Non Finnish (NFE) AF: 0.386 AC: 354018 AN: 917054

Other (OTH) AF: 0.334 AC: 17786 AN: 53176

GnomAD4 genome AF: 0.292 AC: 44345 AN: 152062 Hom.: 7322 Cov.: 32 AF XY: 0.292 AC XY: 21705 AN XY: 74322

African (AFR) AF: 0.145 AC: 5997 AN: 41488

American (AMR) AF: 0.257 AC: 3930 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1195 AN: 3470

East Asian (EAS) AF: 0.108 AC: 557 AN: 5176

South Asian (SAS) AF: 0.283 AC: 1367 AN: 4826

European-Finnish (FIN) AF: 0.417 AC: 4406 AN: 10560

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.379 AC: 25741 AN: 67940

Other (OTH) AF: 0.316 AC: 666 AN: 2106

Alfa AF: 0.326 Hom.: 1075

Bravo AF: 0.273

Asia WGS AF: 0.179 AC: 624 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs140689; hg19: chr18-47800421; COSMIC: COSV54004599; COSMIC: COSV54004599;