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NM_001375380.1(EBF3):c.554+5G>A AND Hypotonia, ataxia, and delayed development syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 2, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002273034.3

Allele description [Variation Report for NM_001375380.1(EBF3):c.554+5G>A]

NM_001375380.1(EBF3):c.554+5G>A

Gene:
EBF3:EBF transcription factor 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q26.3
Genomic location:
Preferred name:
NM_001375380.1(EBF3):c.554+5G>A
HGVS:
  • NC_000010.11:g.129957253C>T
  • NG_030038.1:g.11575G>A
  • NM_001005463.3:c.554+5G>A
  • NM_001375379.1:c.554+5G>A
  • NM_001375380.1:c.554+5G>AMANE SELECT
  • NM_001375389.1:c.554+5G>A
  • NM_001375390.1:c.554+5G>A
  • NM_001375391.1:c.554+5G>A
  • NM_001375392.1:c.554+5G>A
  • NC_000010.10:g.131755517C>T
  • NM_001005463.2:c.554+5G>A
Links:
dbSNP: rs2134610433
NCBI 1000 Genomes Browser:
rs2134610433
Molecular consequence:
  • NM_001005463.3:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001375379.1:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001375380.1:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001375389.1:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001375390.1:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001375391.1:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001375392.1:c.554+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Hypotonia, ataxia, and delayed development syndrome (HADDS)
Identifiers:
MONDO: MONDO:0015021; MedGen: C4310618; OMIM: 617330

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002557588Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Feb 2, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.

Harms FL, Girisha KM, Hardigan AA, Kortüm F, Shukla A, Alawi M, Dalal A, Brady L, Tarnopolsky M, Bird LM, Ceulemans S, Bebin M, Bowling KM, Hiatt SM, Lose EJ, Primiano M, Chung WK, Juusola J, Akdemir ZC, Bainbridge M, Charng WL, Drummond-Borg M, et al.

Am J Hum Genet. 2017 Jan 5;100(1):117-127. doi: 10.1016/j.ajhg.2016.11.012. Epub 2016 Dec 22.

PubMed [citation]
PMID:
28017373
PMCID:
PMC5223027

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557588.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hypotonia, ataxia, and delayed development syndrome (MIM#617330). Variants resulting in a premature termination codon have a loss of function effect on protein, whereas missense variant have been demonstrated to have both loss of function and a dominant negative effect (PMID: 28017373). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Splice in silico tool predictions are inconclusive, and the affected nucleotide is highly conserved. (I) 0705 - No comparable non-canonical splice variants have previous evidence for pathogenicity. However, additional splice variants in this region (c.544+1G>A, c.544+4A>C) have been reported as pathogenic, and noted to be observed in several individuals with EBF3-related conditions. Both variants had arisen de novo (LOVD, ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 23, 2024