Variant 10-129957258-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_001375380.1(EBF3):c.554G>A(p.Arg185Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EBF3
NM_001375380.1 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.88

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EBF3	NM_001375380.1 linkuse as main transcript	c.554G>A	p.Arg185Lys	missense_variant, splice_region_variant	6/17	ENST00000440978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EBF3	ENST00000440978.2 linkuse as main transcript	c.554G>A	p.Arg185Lys	missense_variant, splice_region_variant	6/17	3	NM_001375380.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1449730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720660

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypotonia, ataxia, and delayed development syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Jul 02, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

.;D

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.28

Sift

Benign

0.054

T;D

Sift4G

Benign

0.095

T;T

Polyphen

0.0060

B;.

Vest4

0.75

MutPred

0.48

Gain of methylation at R185 (P = 0.0082);Gain of methylation at R185 (P = 0.0082);

MVP

0.76

MPC

1.3

ClinPred

0.97

GERP RS

6.0

Varity_R

0.60

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.38

Position offset: 0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over