chr10-129840963-GACTGCTGGGGAGT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

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
EBF3NM_001375380.1 linkuse as main transcriptc.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
EBF3ENST00000440978.2 linkuse as main transcriptc.1429_1441del p.Thr477ProfsTer10 frameshift_variant 14/173 NM_001375380.1 ENSP00000387543
EBF3ENST00000368648.8 linkuse as main transcriptc.1402_1414del p.Thr468ProfsTer10 frameshift_variant 15/171 ENSP00000357637 A1Q9H4W6-2
EBF3ENST00000355311.10 linkuse as main transcriptc.1429_1441del p.Thr477ProfsTer10 frameshift_variant 14/165 ENSP00000347463 P4Q9H4W6-1
EBF3ENST00000675373.1 linkuse as main transcriptn.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
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 22, 2024The 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 submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 29, 2024Criteria applied: PVS1,PM2,PS2_MOD,PS4_SUP -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 12, 2022Frameshift 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

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064794961; hg19: chr10-131639227; API