2-148021483-GCTGCTGCTGCTGCTA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001378120.1(MBD5):c.-1099_-1085del 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. 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

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]

ACMG classification

Verdict is Benign. Variant got -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_exome allele frequency = 0.000949 (393/414062) while in subpopulation SAS AF= 0.00243 (148/60968). AF 95% confidence interval is 0.00211. There are 1 homozygotes in gnomad4_exome. There are 236 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD5	NM_001378120.1	c.-1099_-1085del		5_prime_UTR_variant	1/14	ENST00000642680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD5	ENST00000642680.2	c.-1099_-1085del		5_prime_UTR_variant	1/14		NM_001378120.1

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

Gnomad4 AFR exome AF: 0.000357

Gnomad4 AMR exome AF: 0.000652

Gnomad4 ASJ exome AF: 0.000141

Gnomad4 EAS exome AF: 0.000362

Gnomad4 SAS exome AF: 0.00243

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.000715

Gnomad4 OTH exome AF: 0.000383

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

Gnomad4 AFR AF: 0.000437

Gnomad4 AMR AF: 0.000525

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.000758

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.000477

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

MBD5: BS1 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs755361381; hg19: chr2-148779052;