10-129867246-G-A

Position:

• chr10-129867246-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001375380.1(EBF3):​c.934C>T​(p.Arg312*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EBF3 NM_001375380.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.71

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:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-129867246-G-A is Pathogenic according to our data. Variant chr10-129867246-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 423864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-129867246-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.934C>T	p.Arg312*	stop_gained	10/17	ENST00000440978.2	NP_001362309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EBF3	ENST00000440978.2	c.934C>T	p.Arg312*	stop_gained	10/17	3	NM_001375380.1	ENSP00000387543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727168

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: 0.0000187

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotonia, ataxia, and delayed development syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 12, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 03, 2020	The heterozygous p.Arg303Ter variant in EBF3 was identified by our study in 1 individual with hypotonia, ataxia, and delayed development syndrome. Trio genome analysis showed this variant to be de novo. The p.Arg303Ter variant has also been reported in 1 individual of unknown ethnicity with hypotonia, ataxia, and delayed development syndrome (PMID: 28017373), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 423864) as pathogenic by GeneDx. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 28017373). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 303, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the EBF3 gene is strongly associated with hypotonia, ataxia, and delayed development syndrome. In summary, this variant meets criteria to be classified as pathogenic for hypotonia, ataxia, and delayed development syndrome in an autosomal dominant manner based on multiple de novo occurrences in affected individuals, absence of the variant from control populations, and the predicted LOF mechanism for this variant. ACMG/AMP Criteria applied: PS2, PM2, PVS1_strong, PS3_supporting , PS4_supporting (Richards 2015). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect with mislocalization of the truncated EBF3 protein and significantly reduced transcriptional activation of a reporter gene (PMID: 28017373); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28017373, 36937983) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.907C>T (p.R303*) alteration, located in coding exon 10 of the EBF3 gene, consists of a C to T substitution at nucleotide position 907. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 303. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported de novo in multiple individuals with features consistent with EBF3-related neurodevelopmental disorder (Harms, 2017; van der Veen, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.83
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064796669; hg19: chr10-131665510; COSMIC: COSV62475510;