2-148021483-G-GCTGCTGCTGCTGCTA

Variant names:

• chr2-148021483-G-GCTGCTGCTGCTGCTA
• rs755361381
• NM_001378120.1:c.-1099_-1085dupGCTACTGCTGCTGCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001378120.1(MBD5):​c.-1099_-1085dupGCTACTGCTGCTGCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 565,666 control chromosomes in the GnomAD database, including 17 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0025 (16 hom.)
• Consequence: MBD5 NM_001378120.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.437
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-148021483-G-GCTGCTGCTGCTGCTA is Benign according to our data. Variant chr2-148021483-G-GCTGCTGCTGCTGCTA is described in ClinVar as [Likely_benign]. Clinvar id is 2651401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00204 (309/151574) while in subpopulation NFE AF = 0.00253 (172/67880). AF 95% confidence interval is 0.00222. There are 1 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-1099_-1085dupGCTACTGCTGCTGCT		5_prime_UTR_variant	Exon 1 of 14	ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-1099_-1085dupGCTACTGCTGCTGCT		5_prime_UTR_variant	Exon 1 of 14		NM_001378120.1	ENSP00000493871.2

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 310 AN: 151454 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.00249 AC: 1031 AN: 414092 Hom.: 16 Cov.: 0 AF XY: 0.00234 AC XY: 537 AN XY: 229134

African (AFR) AF: 0.00197 AC: 22 AN: 11190

American (AMR) AF: 0.00173 AC: 53 AN: 30688

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 44 AN: 14206

East Asian (EAS) AF: 0.00229 AC: 38 AN: 16564

South Asian (SAS) AF: 0.000984 AC: 60 AN: 60974

European-Finnish (FIN) AF: 0.00191 AC: 62 AN: 32532

Middle Eastern (MID) AF: 0.00155 AC: 3 AN: 1938

European-Non Finnish (NFE) AF: 0.00313 AC: 704 AN: 225106

Other (OTH) AF: 0.00215 AC: 45 AN: 20894

GnomAD4 genome AF: 0.00204 AC: 309 AN: 151574 Hom.: 1 Cov.: 29 AF XY: 0.00205 AC XY: 152 AN XY: 74092

African (AFR) AF: 0.00153 AC: 63 AN: 41180

American (AMR) AF: 0.00223 AC: 34 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5160

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4790

European-Finnish (FIN) AF: 0.00171 AC: 18 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 67880

Other (OTH) AF: 0.00143 AC: 3 AN: 2096

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBD5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755361381; hg19: chr2-148779052;