rs1057519520
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate
The NM_001375380.1(EBF3):c.579G>T(p.Lys193Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K193E) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
EBF3
NM_001375380.1 missense
NM_001375380.1 missense
Scores
8
7
3
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
EBF3 (HGNC:19087): (EBF transcription factor 3) This gene encodes a member of the early B-cell factor (EBF) family of DNA binding transcription factors. EBF proteins are involved in B-cell differentiation, bone development and neurogenesis, and may also function as tumor suppressors. The encoded protein inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis, and aberrant methylation or deletion of this gene may play a role in multiple malignancies including glioblastoma multiforme and gastric carcinoma. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001375380.1
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr10-129877827-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267357.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
Missense variant where missense usually causes diseases, EBF3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.829
PP5
?
Variant 10-129877825-C-A is Pathogenic according to our data. Variant chr10-129877825-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 375501.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-129877825-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EBF3 | NM_001375380.1 | c.579G>T | p.Lys193Asn | missense_variant | 7/17 | ENST00000440978.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EBF3 | ENST00000440978.2 | c.579G>T | p.Lys193Asn | missense_variant | 7/17 | 3 | NM_001375380.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypotonia, ataxia, and delayed development syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 07, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2023 | In vitro studies indicate that the K193N variant may reduce binding affinity to the CD79a promoter resulting in reduced transcriptional activation (Sleven et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28135719, 28191890, 28017370, 31785789, 33102976, 34367240) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Loss of methylation at K193 (P = 0.0013);Loss of methylation at K193 (P = 0.0013);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at