chr18-50273360-C-G

Variant names:

• chr18-50273360-C-G
• rs767264726
• NM_015846.4:c.1558G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015846.4(MBD1):​c.1558G>C​(p.Val520Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V520I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MBD1 NM_015846.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.732
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.115478635).

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.1558G>C	p.Val520Leu	missense	Exon 13 of 17	NP_056671.2
	MBD1	NM_001323942.2		c.1633G>C	p.Val545Leu	missense	Exon 14 of 17	NP_001310871.1	A0A994J7H0
	MBD1	NM_001323947.2		c.1588G>C	p.Val530Leu	missense	Exon 14 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.1558G>C	p.Val520Leu	missense	Exon 13 of 17	ENSP00000269468.5	Q9UIS9-1
	MBD1	ENST00000590208.5	TSL:1	c.1558G>C	p.Val520Leu	missense	Exon 13 of 16	ENSP00000468785.1	Q9UIS9-12
	MBD1	ENST00000585672.5	TSL:1	c.1408G>C	p.Val470Leu	missense	Exon 12 of 15	ENSP00000466092.1	Q9UIS9-10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.52	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.73
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.23
Sift	Benign	0.27	T
Sift4G	Benign	0.34	T
Polyphen		0.11	B
Vest4		0.24
MVP		0.48
MPC		0.65
ClinPred		0.074	T
GERP RS		2.9
Varity_R		0.023
gMVP		0.042
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs767264726; hg19: chr18-47799730;