10-129840963-GACTGCTGGGGAGT-G

Position:

• chr10-129840963-GACTGCTGGGGAGT-G

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.1429_1441del​(p.Thr477ProfsTer10) 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 (★★). 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

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 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 10-129840963-GACTGCTGGGGAGT-G is Pathogenic according to our data. Variant chr10-129840963-GACTGCTGGGGAGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 421178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.1429_1441del	p.Thr477ProfsTer10	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.1429_1441del	p.Thr477ProfsTer10	frameshift_variant	14/17	3	NM_001375380.1	ENSP00000387543
EBF3	ENST00000368648.8	c.1402_1414del	p.Thr468ProfsTer10	frameshift_variant	15/17	1		ENSP00000357637	A1
EBF3	ENST00000355311.10	c.1429_1441del	p.Thr477ProfsTer10	frameshift_variant	14/16	5		ENSP00000347463	P4
EBF3	ENST00000675373.1	n.1074_1086del		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: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 29, 2024

Criteria applied: PVS1,PM2,PS2_MOD,PS4_SUP -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2022

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064794961; hg19: chr10-131639227;