Genetic Variant EBF3:p.Arg163Gly (chr10-129957323-CCG-TCC) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is . The variant received 6 ACMG points: 6P and 0B. PM1PM5PP2PP3

The NM_001375380.1(EBF3):c.487_489delCGGinsGGA(p.Arg163Gly) variant causes a missense, splice region 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

EBF3
NM_001375380.1 missense, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.96

Publications

0 publications found

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]

EBF3 Gene-Disease associations (from GenCC):

hypotonia, ataxia, and delayed development syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia

EBF3 links:

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new If you want to explore the variant's impact on the transcript NM_001375380.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001375380.1

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-129957324-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 375500.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the EBF3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 3.6113 (above the threshold of 3.09). Trascript score misZ: 3.1409 (above the threshold of 3.09). GenCC associations: The gene is linked to hypotonia, ataxia, and delayed development syndrome.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EBF3	NM_001375380.1	MANE Select	c.487_489delCGGinsGGA	p.Arg163Gly	missense splice_region	N/A	NP_001362309.1	H0Y3W9
EBF3	NM_001375379.1		c.487_489delCGGinsGGA	p.Arg163Gly	missense splice_region	N/A	NP_001362308.1	Q9H4W6-1
EBF3	NM_001375389.1		c.487_489delCGGinsGGA	p.Arg163Gly	missense splice_region	N/A	NP_001362318.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EBF3	ENST00000440978.2	TSL:3 MANE Select	c.487_489delCGGinsGGA	p.Arg163Gly	missense splice_region	N/A	ENSP00000387543.2	H0Y3W9
EBF3	ENST00000368648.8	TSL:1	c.487_489delCGGinsGGA	p.Arg163Gly	missense splice_region	N/A	ENSP00000357637.3	Q9H4W6-2
EBF3	ENST00000904893.1		c.487_489delCGGinsGGA	p.Arg163Gly	missense splice_region	N/A	ENSP00000574952.1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over