2-148021483-GCTGCTGCTGCTGCTA-G

Variant names:

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

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_-1085delGCTACTGCTGCTGCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00091 in 565,638 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.00080 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00095 (1 hom.)
• Consequence: MBD5 NM_001378120.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.96
• 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-GCTGCTGCTGCTGCTA-G is Benign according to our data. Variant chr2-148021483-GCTGCTGCTGCTGCTA-G is described in ClinVar as [Likely_benign]. Clinvar id is 2651402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000805 (122/151576) while in subpopulation SAS AF = 0.00188 (9/4790). AF 95% confidence interval is 0.000979. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 122 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000799 AC: 121 AN: 151456 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.000758

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000949 AC: 393 AN: 414062 Hom.: 1 AF XY: 0.00103 AC XY: 236 AN XY: 229116

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000357 AC: 4 AN: 11190

American (AMR) AF: 0.000652 AC: 20 AN: 30690

Ashkenazi Jewish (ASJ) AF: 0.000141 AC: 2 AN: 14210

East Asian (EAS) AF: 0.000362 AC: 6 AN: 16564

South Asian (SAS) AF: 0.00243 AC: 148 AN: 60968

European-Finnish (FIN) AF: 0.00129 AC: 42 AN: 32518

Middle Eastern (MID) AF: 0.00103 AC: 2 AN: 1936

European-Non Finnish (NFE) AF: 0.000715 AC: 161 AN: 225096

Other (OTH) AF: 0.000383 AC: 8 AN: 20890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000805 AC: 122 AN: 151576 Hom.: 0 Cov.: 29 AF XY: 0.000931 AC XY: 69 AN XY: 74094

African (AFR) AF: 0.000437 AC: 18 AN: 41180

American (AMR) AF: 0.000525 AC: 8 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4790

European-Finnish (FIN) AF: 0.000758 AC: 8 AN: 10552

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

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 67880

Other (OTH) AF: 0.000477 AC: 1 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

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBD5: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=294/6	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;