rs1057519389

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-129957324-C-A
• chr10-129957324-C-G
• chr10-129957324-C-T

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>T​(p.Arg163Leu) 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. R163P) 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:4 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-G 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, 0.828
• PP5: Variant 10-129957324-C-A is Pathogenic according to our data. Variant chr10-129957324-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 268155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-129957324-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.488G>T	p.Arg163Leu	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>T	p.Arg163Leu	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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R163L variant in the EBF3 gene has been reported previously as a de novo variant in a female child with global developmental delay, congenital hypotonia, torticollis, facial weakness, dysphagia, dysmorphic features including triangular facies, and a normal brain MRI (Chao et al., 2017). The R163L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R163L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R163L as a pathogenic variant. -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 13, 2017

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 seen once in our laboratory de novo in a 1-year-old female with global delays, hypotonia, dysmorphic features, eye anomalies (esotropia, presbyopia) and palpable liver. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;.
Vest4		0.89
MutPred		0.32		Loss of disorder (P = 0.048);Loss of disorder (P = 0.048);
MVP		0.82
MPC		2.7
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;