rs1057519092

Variant names:

• chr10-129957325-G-A
• rs1057519092
• NM_001375380.1:c.487C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-129957325-G-A
• chr10-129957325-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3 PP5

The NM_001375380.1(EBF3):​c.487C>T​(p.Arg163Trp) 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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
• Scores: Splicing: ADA: 0.9871
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 9.96

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 Likely_pathogenic. Variant got 7 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 10-129957325-G-A is Pathogenic according to our data. Variant chr10-129957325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374797.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.487C>T	p.Arg163Trp	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.487C>T	p.Arg163Trp	missense_variant, splice_region_variant	Exon 6 of 17	3	NM_001375380.1	ENSP00000387543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

-

Sezerman Lab, Dept of Biostatistics and Bioinformatics, Acibadem Mehmet Ali Aydinlar University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant R163W was reported in a girl by Blackburn et. al. They also showed the impact of the variant on protein structure. Their findings demonstrated that p.R163W could cause decreased DNA binding affinity and differential transcriptional activation. In summary, R163W is classified as pathogenic based on the previous studies and our segregation study that shows the absence of the variant in the biological parents of the proband. -

Sep 23, 2021

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Recurrent variants affecting codon 163 are located in a CpG island, a mutational hotspot -

not provided Pathogenic:1

Aug 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28487885, 37532691, 35340043, 33102976, 33144682) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.0088	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.40		Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);
MVP		0.82
MPC		2.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.81
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.0		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: rs1057519092; hg19: chr10-131755589;