10-129957324-C-T

Variant names:

• chr10-129957324-C-T
• rs1057519389
• NM_001375380.1:c.488G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001375380.1(EBF3):​c.488G>A​(p.Arg163Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EBF3 NM_001375380.1 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.88

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-129957324-C-A is described in Lovd as [Pathogenic].
• 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: MetaRNN computational evidence supports a deleterious effect, 0.753
• PP5: Variant 10-129957324-C-T is Pathogenic according to our data. Variant chr10-129957324-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 268156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-129957324-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.488G>A	p.Arg163Gln	missense_variant, splice_region_variant	Exon 6 of 17	ENST00000440978.2	NP_001362309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EBF3	ENST00000440978.2	c.488G>A	p.Arg163Gln	missense_variant, splice_region_variant	Exon 6 of 17	3	NM_001375380.1	ENSP00000387543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotonia, ataxia, and delayed development syndrome Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 27, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This patient has been reported in PMID 28017372. -

Feb 23, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dyssynergia;C0026827:Hypotonia;C0454641:Expressive language delay;C0557874:Global developmental delay;C3714756:Intellectual disability Pathogenic:1

Aug 25, 2016

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was found once in our laboratory de novo in a 1-year-old female with hypotonia, developmental delay, failure to thrive, and dysmorphic features. -

Inborn genetic diseases Pathogenic:1

Dec 28, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that R163Q mutant protein impairs transcriptional activation, consistent with a loss of function effect (Chao et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34050706, 28017372, 30011838, 29062322, 28487885, 28017373, 28017370, 20300201, 31498321, 29162653, 19627984, 26582918) -

Isolated Pierre-Robin syndrome Pathogenic:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg163Gln variant was identified by our study in one individual with Robin sequence and severe hypotonia with abnormal brain MRI findings. Trio analysis showed this variant occurred de novo. The p.Arg163Gln variant is located in the transcription factor EBF3 and occurs adjacent to a (de novo) ClinVar pathogenic variant for HADDS. The arginine (and adjacent serine) is highly conserved at the amino acid level and the nucleotide position is also highly conserved. The variant occurs in the conserved DNA binding and dimerization (homodimer) domains. Additionally, the c.488G>A variant occurs 2 nucleotides from the splice acceptor site of intron 5 so the missense variants in this region could potentially be functioning in a LoF mechanism and which may lead to slightly more mild phenotypes than the dominant negative acting missense variants in this gene. Additionally, of the first 3 initial papers describing this disorder, two patients had a G>A at the same position (PMID: 28017372) while another patient had a G>C at the same nucleotide position resulting in a p.Arg163Pro (PMID: 28017370). In summary, taken together, the evidence available suggest this variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.97	D;.
Vest4		0.89
MutPred		0.27		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.77
MPC		1.9
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.55
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519389; hg19: chr10-131755588;