rs1057520964

Variant names:

• chr2-148021062-C-A
• rs1057520964
• ENST00000407073.5:c.-962+16C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-148021062-C-A
• chr2-148021062-C-T

Variant summary

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

The ENST00000407073.5(MBD5):​c.-962+16C>A variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MBD5 ENST00000407073.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56
• Publications: 1 publications found

Genes affected

MBD5 (HGNC:20444): (methyl-CpG binding domain protein 5) This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

ORC4 (HGNC:8490): (origin recognition complex subunit 4) The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]

ORC4 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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 (BayesDel_noAF=-0.29).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-1547C>A		upstream_gene_variant		ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-1547C>A		upstream_gene_variant			NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1750 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1206

African (AFR) AF: 0.00 AC: 0 AN: 28

American (AMR) AF: 0.00 AC: 0 AN: 128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22

East Asian (EAS) AF: 0.00 AC: 0 AN: 20

South Asian (SAS) AF: 0.00 AC: 0 AN: 632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 640

Other (OTH) AF: 0.00 AC: 0 AN: 46

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		3.6
PromoterAI		0.0063	Neutral

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: rs1057520964; hg19: chr2-148778631;