10-129840949-CTG-C

Position:

• chr10-129840949-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001375380.1(EBF3):​c.1454_1455del​(p.Thr485SerfsTer4) 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EBF3 NM_001375380.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 10-129840949-CTG-C is Pathogenic according to our data. Variant chr10-129840949-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2674611.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.1454_1455del	p.Thr485SerfsTer4	frameshift_variant	14/17	ENST00000440978.2	NP_001362309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EBF3	ENST00000440978.2	c.1454_1455del	p.Thr485SerfsTer4	frameshift_variant	14/17	3	NM_001375380.1	ENSP00000387543
EBF3	ENST00000368648.8	c.1427_1428del	p.Thr476SerfsTer4	frameshift_variant	15/17	1		ENSP00000357637	A1
EBF3	ENST00000355311.10	c.1454_1455del	p.Thr485SerfsTer4	frameshift_variant	14/16	5		ENSP00000347463	P4
EBF3	ENST00000675373.1	n.1099_1100del		non_coding_transcript_exon_variant	11/14

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypotonia, ataxia, and delayed development syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Apr 09, 2020

The c.1427_1428delCA (p.Thr476SerfsTer4) variant in the EBF3 gene is a heterozygous frameshift variant, resulting in a premature stop codon downstream. This variant localizes to coding exon 14 of the gene (16 coding exons in total; NM_001005463.3). This variant is absent in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. To the best of our knowledge, this specific variant has not been described in the literature to be associated with disease. However, loss-of-function variants in EBF3 have been established to be disease causing (PMID: 29162653). A nearby variant (p.Thr464Profs*10) has been reported in an affected individual (PMID: 29162653). No loss-of-function variants downstream to this one have been reported in affected individuals. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-131639213;