10-129837958-T-A

Variant names:

• chr10-129837958-T-A
• rs1472885479
• ENST00000368648.8:c.1627A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001375379.1(EBF3):​c.1762A>T​(p.Met588Leu) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M588V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EBF3 NM_001375379.1 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.95
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypotonia, ataxia, and delayed development syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ENSG00000300012 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: 3.1001 (above the threshold of 3.09). GenCC associations: The gene is linked to hypotonia, ataxia, and delayed development syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29467207).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375379.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBF3	NM_001375380.1	MANE Select	c.1875A>T	p.Leu625Leu	splice_region synonymous	Exon 17 of 17	NP_001362309.1	H0Y3W9
	EBF3	NM_001375379.1		c.1762A>T	p.Met588Leu	missense splice_region	Exon 16 of 16	NP_001362308.1	Q9H4W6-1
	EBF3	NM_001375391.1		c.1654A>T	p.Met552Leu	missense splice_region	Exon 16 of 16	NP_001362320.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBF3	ENST00000368648.8	TSL:1	c.1627A>T	p.Met543Leu	missense splice_region	Exon 17 of 17	ENSP00000357637.3	Q9H4W6-2
	EBF3	ENST00000440978.2	TSL:3 MANE Select	c.1875A>T	p.Leu625Leu	splice_region synonymous	Exon 17 of 17	ENSP00000387543.2	H0Y3W9
	EBF3	ENST00000355311.10	TSL:5	c.1762A>T	p.Met588Leu	missense splice_region	Exon 16 of 16	ENSP00000347463.4	Q9H4W6-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.20
Sift	Benign	0.050	D
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.48
MutPred		0.19		Loss of catalytic residue at M543 (P = 0.0405)
MVP		0.78
MPC		1.3
ClinPred		0.75	D
GERP RS		6.1
Varity_R		0.32
gMVP		0.38
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs1472885479; hg19: chr10-131636222;