10-129841024-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001375380.1(EBF3):c.1381A>G(p.Ser461Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EBF3 NM_001375380.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EBF3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EBF3	NM_001375380.1	c.1381A>G	p.Ser461Gly	missense_variant	14/17	ENST00000440978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EBF3	ENST00000440978.2	c.1381A>G	p.Ser461Gly	missense_variant	14/17	3	NM_001375380.1
EBF3	ENST00000368648.8	c.1354A>G	p.Ser452Gly	missense_variant	15/17	1		A1
EBF3	ENST00000355311.10	c.1381A>G	p.Ser461Gly	missense_variant	14/16	5		P4
EBF3	ENST00000675373.1	n.1026A>G		non_coding_transcript_exon_variant	11/14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236506 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447336 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000371 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.014
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.27
Sift	Benign	0.14	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;.
Vest4		0.69
MutPred		0.21		Loss of glycosylation at S452 (P = 0.0235);.;
MVP		0.66
MPC		0.62
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.27
gMVP		0.80

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: rs1406490086; hg19: chr10-131639288;