rs145475623

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001378120.1(MBD5):​c.3842C>T​(p.Thr1281Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000645 in 1,614,206 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00068 ( 3 hom. )

Consequence

MBD5
NM_001378120.1 missense

Scores

2
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:6

Conservation

PhyloP100: 3.14
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0380328).
BP6
Variant 2-148489474-C-T is Benign according to our data. Variant chr2-148489474-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 206095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MBD5NM_001378120.1 linkuse as main transcriptc.3842C>T p.Thr1281Ile missense_variant 11/14 ENST00000642680.2 NP_001365049.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MBD5ENST00000642680.2 linkuse as main transcriptc.3842C>T p.Thr1281Ile missense_variant 11/14 NM_001378120.1 ENSP00000493871

Frequencies

GnomAD3 genomes
AF:
0.000348
AC:
53
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000676
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000481
AC:
121
AN:
251428
Hom.:
0
AF XY:
0.000515
AC XY:
70
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000950
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000676
AC:
988
AN:
1461888
Hom.:
3
Cov.:
32
AF XY:
0.000701
AC XY:
510
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.000833
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.000348
AC:
53
AN:
152318
Hom.:
0
Cov.:
32
AF XY:
0.000295
AC XY:
22
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000676
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000757
Hom.:
2
Bravo
AF:
0.000351
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000552
AC:
67
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000545
EpiControl
AF:
0.000830

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 18, 2020This variant is associated with the following publications: (PMID: 17847001, 21981781, 27222293) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024MBD5: BP4, BS1 -
Uncertain significance, flagged submissionclinical testingEurofins Ntd Llc (ga)Apr 11, 2017- -
MBD5 associated neurodevelopmental disorder Pathogenic:1
Likely pathogenic, flagged submissionresearchElsea Laboratory, Baylor College of MedicineOct 01, 2012- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 25, 2016- -
Intellectual disability, autosomal dominant 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024- -
MBD5-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 14, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 09, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.023
T;.;.;T
Eigen
Benign
-0.20
Eigen_PC
Benign
0.056
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.82
T;.;T;T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.038
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;.;.;.
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.60
N;.;.;N
REVEL
Benign
0.045
Sift
Benign
0.18
T;.;.;T
Sift4G
Benign
0.11
T;.;.;T
Polyphen
0.0040
B;.;.;B
Vest4
0.23
MVP
0.10
MPC
0.17
ClinPred
0.020
T
GERP RS
5.9
Varity_R
0.10
gMVP
0.15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145475623; hg19: chr2-149247043; API