10-129867225-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001375380.1(EBF3):​c.955C>T​(p.His319Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

EBF3
NM_001375380.1 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.90
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]
EBF3-AS1 (HGNC:56218): (EBF3 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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). The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the gene with hypotonia, ataxia, and delayed development syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EBF3NM_001375380.1 linkc.955C>T p.His319Tyr missense_variant 10/17 ENST00000440978.2 NP_001362309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EBF3ENST00000440978.2 linkc.955C>T p.His319Tyr missense_variant 10/173 NM_001375380.1 ENSP00000387543.2 H0Y3W9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

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 GeneticsJun 21, 2022The c.928C>T (p.H310Y) alteration is located in exon 10 (coding exon 10) of the EBF3 gene. This alteration results from a C to T substitution at nucleotide position 928, causing the histidine (H) at amino acid position 310 to be replaced by a tyrosine (Y). 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
0.95
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
.;D
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.0045
T
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.1
.;M
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-4.7
D;D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0010
D;D
Sift4G
Benign
0.10
T;T
Polyphen
0.91
P;.
Vest4
0.83
MutPred
0.57
Loss of disorder (P = 0.044);.;
MVP
0.60
MPC
1.4
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.94
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: chr10-131665489; API