rs1057519518

Positions:

• chr10-129963462-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001375380.1(EBF3):​c.196A>G​(p.Asn66Asp) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EBF3 NM_001375380.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.21

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]

EBF3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EBF3. . Gene score misZ 3.6113 (greater than the threshold 3.09). Trascript score misZ 3.1409 (greater than threshold 3.09). GenCC has associacion of gene with hypotonia, ataxia, and delayed development syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 10-129963462-T-C is Pathogenic according to our data. Variant chr10-129963462-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375495.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-129963462-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EBF3	NM_001375380.1	c.196A>G	p.Asn66Asp	missense_variant	2/17	ENST00000440978.2	NP_001362309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EBF3	ENST00000440978.2	c.196A>G	p.Asn66Asp	missense_variant	2/17	3	NM_001375380.1	ENSP00000387543.2
EBF3	ENST00000368648.8	c.196A>G	p.Asn66Asp	missense_variant	3/17	1		ENSP00000357637.3
EBF3	ENST00000355311.10	c.196A>G	p.Asn66Asp	missense_variant	2/16	5		ENSP00000347463.4
EBF3	ENST00000682649.1	n.146A>G		non_coding_transcript_exon_variant	2/12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436948 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2018

- -

Hypotonia, ataxia, and delayed development syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.82
MutPred		0.71		Gain of ubiquitination at K64 (P = 0.0359);Gain of ubiquitination at K64 (P = 0.0359);
MVP		0.63
MPC		2.6
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.88
gMVP		0.97

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: rs1057519518; hg19: chr10-131761726;