10-129840963-GACTGCTGGGGAGT-G

Variant names:

• chr10-129840963-GACTGCTGGGGAGT-G
• rs1064794961
• NM_001375380.1:c.1429_1441delACTCCCCAGCAGT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001375380.1(EBF3):​c.1429_1441delACTCCCCAGCAGT​(p.Thr477ProfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EBF3 NM_001375380.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hypotonia, ataxia, and delayed development syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-129840963-GACTGCTGGGGAGT-G is Pathogenic according to our data. Variant chr10-129840963-GACTGCTGGGGAGT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 421178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375380.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBF3	NM_001375380.1	MANE Select	c.1429_1441delACTCCCCAGCAGT	p.Thr477ProfsTer10	frameshift	Exon 14 of 17	NP_001362309.1
	EBF3	NM_001375379.1		c.1429_1441delACTCCCCAGCAGT	p.Thr477ProfsTer10	frameshift	Exon 14 of 16	NP_001362308.1
	EBF3	NM_001375389.1		c.1429_1441delACTCCCCAGCAGT	p.Thr477ProfsTer10	frameshift	Exon 14 of 17	NP_001362318.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBF3	ENST00000440978.2	TSL:3 MANE Select	c.1429_1441delACTCCCCAGCAGT	p.Thr477ProfsTer10	frameshift	Exon 14 of 17	ENSP00000387543.2
	EBF3	ENST00000368648.8	TSL:1	c.1402_1414delACTCCCCAGCAGT	p.Thr468ProfsTer10	frameshift	Exon 15 of 17	ENSP00000357637.3
	EBF3	ENST00000355311.10	TSL:5	c.1429_1441delACTCCCCAGCAGT	p.Thr477ProfsTer10	frameshift	Exon 14 of 16	ENSP00000347463.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Apr 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1402_1414del13 (p.T468Pfs*10) alteration, located in exon 14 (coding exon 14) of the EBF3 gene, consists of a deletion of 13 nucleotides from position 1402 to 1414, causing a translational frameshift with a predicted alternate stop codon after 10 amino acids. 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 has been determined to be the result of a de novo mutation in one individual with features consistent with EBF3-related neurodevelopmental disorder (Tanaka, 2017). Based on the available evidence, this alteration is classified as pathogenic.

Hypotonia, ataxia, and delayed development syndrome Pathogenic:1

Aug 29, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM2,PS2_MOD,PS4_SUP

not provided Pathogenic:1

Apr 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29162653)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1064794961; hg19: chr10-131639227;