10-129957324-C-G

Variant names:

• chr10-129957324-C-G
• rs1057519389
• NM_001375380.1:c.488G>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.488G>C​(p.Arg163Pro) 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 (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
• Clinical Significance: Pathogenic no assertion criteria provided P:1 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 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: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 10-129957324-C-G is Pathogenic according to our data. Variant chr10-129957324-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 375500.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-129957324-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.488G>C	p.Arg163Pro	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>C	p.Arg163Pro	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:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 07, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.87	P;.
Vest4		0.93
MutPred		0.35		Gain of methylation at K168 (P = 0.0783);Gain of methylation at K168 (P = 0.0783);
MVP		0.82
MPC		3.0
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1057519389; hg19: chr10-131755588;