rs1057519521

Variant names:

• chr10-129963374-TTCTC-T
• rs1057519521
• NM_001375380.1:c.280_283delGAGA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001375380.1(EBF3):​c.280_283delGAGA​(p.Glu94LysfsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EBF3 NM_001375380.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.28
• 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 11 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 10-129963374-TTCTC-T is Pathogenic according to our data. Variant chr10-129963374-TTCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 375502.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.280_283delGAGA	p.Glu94LysfsTer37	frameshift_variant	Exon 2 of 17	ENST00000440978.2	NP_001362309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EBF3	ENST00000440978.2	c.280_283delGAGA	p.Glu94LysfsTer37	frameshift_variant	Exon 2 of 17	3	NM_001375380.1	ENSP00000387543.2
EBF3	ENST00000368648.8	c.280_283delGAGA	p.Glu94LysfsTer37	frameshift_variant	Exon 3 of 17	1		ENSP00000357637.3
EBF3	ENST00000355311.10	c.280_283delGAGA	p.Glu94LysfsTer37	frameshift_variant	Exon 2 of 16	5		ENSP00000347463.4
EBF3	ENST00000682649.1	n.230_233delGAGA		non_coding_transcript_exon_variant	Exon 2 of 12

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:2

Revision: no assertion criteria provided

Submissions by phenotype

Constipation;C0042580:Vesicoureteral reflux;C0262361:Growth abnormality;C0262655:Recurrent urinary tract infections;C0424503:Abnormal facial shape;C0557874:Global developmental delay;C1858120:Generalized hypotonia Pathogenic:1

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NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hypotonia, ataxia, and delayed development syndrome Pathogenic:1

Feb 07, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1057519521; hg19: chr10-131761638;