NM_001375380.1:c.1436A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001375380.1(EBF3):ā€‹c.1436A>Gā€‹(p.Gln479Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

EBF3
NM_001375380.1 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the EBF3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.6113 (above the threshold of 3.09). Trascript score misZ: 3.1409 (above the threshold of 3.09). GenCC associations: The gene is linked to hypotonia, ataxia, and delayed development syndrome.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EBF3NM_001375380.1 linkc.1436A>G p.Gln479Arg missense_variant Exon 14 of 17 ENST00000440978.2 NP_001362309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EBF3ENST00000440978.2 linkc.1436A>G p.Gln479Arg missense_variant Exon 14 of 17 3 NM_001375380.1 ENSP00000387543.2 H0Y3W9
EBF3ENST00000368648.8 linkc.1409A>G p.Gln470Arg missense_variant Exon 15 of 17 1 ENSP00000357637.3 Q9H4W6-2
EBF3ENST00000355311.10 linkc.1436A>G p.Gln479Arg missense_variant Exon 14 of 16 5 ENSP00000347463.4 Q9H4W6-1
EBF3ENST00000675373.1 linkn.1081A>G non_coding_transcript_exon_variant Exon 11 of 14

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461730
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727166
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 29, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1409A>G (p.Q470R) alteration is located in exon 14 (coding exon 14) of the EBF3 gene. This alteration results from a A to G substitution at nucleotide position 1409, causing the glutamine (Q) at amino acid position 470 to be replaced by an arginine (R). 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
0.63
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
.;T
Eigen
Benign
0.087
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.0066
T
MetaRNN
Uncertain
0.62
D;D
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.8
.;L
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.7
N;N
REVEL
Uncertain
0.31
Sift
Uncertain
0.0090
D;D
Sift4G
Benign
0.25
T;T
Polyphen
0.0010
B;.
Vest4
0.82
MutPred
0.21
Gain of MoRF binding (P = 0.0544);.;
MVP
0.77
MPC
0.70
ClinPred
0.93
D
GERP RS
4.8
Varity_R
0.35
gMVP
0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-131639233; API