chr10-129840255-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001375380.1(EBF3):ā€‹c.1749T>Gā€‹(p.Asn583Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000321 in 1,559,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

EBF3
NM_001375380.1 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EBF3. . Gene score misZ 3.6113 (greater than the threshold 3.09). Trascript score misZ 3.1409 (greater than threshold 3.09). GenCC has associacion of gene with hypotonia, ataxia, and delayed development syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.2645678).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EBF3NM_001375380.1 linkuse as main transcriptc.1749T>G p.Asn583Lys missense_variant 15/17 ENST00000440978.2 NP_001362309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EBF3ENST00000440978.2 linkuse as main transcriptc.1749T>G p.Asn583Lys missense_variant 15/173 NM_001375380.1 ENSP00000387543
EBF3ENST00000368648.8 linkuse as main transcriptc.1614T>G p.Asn538Lys missense_variant 16/171 ENSP00000357637 A1Q9H4W6-2
EBF3ENST00000355311.10 linkuse as main transcriptc.1749T>G p.Asn583Lys missense_variant 15/165 ENSP00000347463 P4Q9H4W6-1
EBF3ENST00000675373.1 linkuse as main transcriptn.1286T>G non_coding_transcript_exon_variant 12/14

Frequencies

GnomAD3 genomes
AF:
0.0000199
AC:
3
AN:
151012
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000443
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000142
AC:
2
AN:
1408096
Hom.:
0
Cov.:
37
AF XY:
0.00000144
AC XY:
1
AN XY:
696724
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000185
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000199
AC:
3
AN:
151012
Hom.:
0
Cov.:
33
AF XY:
0.0000271
AC XY:
2
AN XY:
73738
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000443
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000835
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 28, 2023The c.1614T>G (p.N538K) alteration is located in exon 15 (coding exon 15) of the EBF3 gene. This alteration results from a T to G substitution at nucleotide position 1614, causing the asparagine (N) at amino acid position 538 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
.;T
Eigen
Benign
-0.063
Eigen_PC
Benign
-0.068
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.26
T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Uncertain
2.1
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.12
Sift
Uncertain
0.0060
D;D
Sift4G
Benign
0.20
T;T
Polyphen
0.061
B;.
Vest4
0.40
MutPred
0.21
Gain of ubiquitination at N538 (P = 0.0018);.;
MVP
0.41
MPC
0.94
ClinPred
0.80
D
GERP RS
3.1
Varity_R
0.21
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs771038634; hg19: chr10-131638519; API