10-129837960-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BS1_SupportingBS2

The ENST00000368648.8(EBF3):​c.1625C>T​(p.Ala542Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

EBF3
ENST00000368648.8 missense, splice_region

Scores

2
6
11
Splicing: ADA: 0.9951
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.92
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 Likely_benign. Variant got -3 ACMG points.

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 3.1106 (greater than threshold 3.09). GenCC has associacion of gene with hypotonia, ataxia, and delayed development syndrome.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000197 (3/152218) while in subpopulation SAS AF= 0.000414 (2/4836). AF 95% confidence interval is 0.0000728. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EBF3NM_001375380.1 linkuse as main transcriptc.1873C>T p.Leu625= splice_region_variant, synonymous_variant 17/17 ENST00000440978.2 NP_001362309.1
LOC107984281XR_001747650.2 linkuse as main transcriptn.6369-487G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EBF3ENST00000368648.8 linkuse as main transcriptc.1625C>T p.Ala542Val missense_variant, splice_region_variant 17/171 ENSP00000357637 A1Q9H4W6-2
EBF3ENST00000440978.2 linkuse as main transcriptc.1873C>T p.Leu625= splice_region_variant, synonymous_variant 17/173 NM_001375380.1 ENSP00000387543
EBF3ENST00000355311.10 linkuse as main transcriptc.1760C>T p.Ala587Val missense_variant, splice_region_variant 16/165 ENSP00000347463 P4Q9H4W6-1
EBF3ENST00000675373.1 linkuse as main transcriptn.1515C>T splice_region_variant, non_coding_transcript_exon_variant 14/14

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152218
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:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251222
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135840
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461758
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000927
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
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:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

Hypotonia, ataxia, and delayed development syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
.;T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.30
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.26
Sift
Uncertain
0.024
D;T
Sift4G
Benign
0.21
T;T
Polyphen
0.0020
B;.
Vest4
0.63
MVP
0.54
MPC
0.76
ClinPred
0.65
D
GERP RS
6.1
Varity_R
0.12
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.87
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: rs148915750; hg19: chr10-131636224; API