NM_001375380.1:c.1749T>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001375380.1(EBF3):c.1749T>G(p.Asn583Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000321 in 1,559,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EBF3
NM_001375380.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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: 3.1409 (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=0.2645678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBF3	NM_001375380.1 link	c.1749T>G	p.Asn583Lys	missense_variant	Exon 15 of 17	ENST00000440978.2	NP_001362309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EBF3	ENST00000440978.2 link	c.1749T>G	p.Asn583Lys	missense_variant	Exon 15 of 17	3	NM_001375380.1	ENSP00000387543.2	H0Y3W9
EBF3	ENST00000368648.8 link	c.1614T>G	p.Asn538Lys	missense_variant	Exon 16 of 17	1		ENSP00000357637.3	Q9H4W6-2
EBF3	ENST00000355311.10 link	c.1749T>G	p.Asn583Lys	missense_variant	Exon 15 of 16	5		ENSP00000347463.4	Q9H4W6-1
EBF3	ENST00000675373.1 link	n.1286T>G		non_coding_transcript_exon_variant	Exon 12 of 14

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

151012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1408096

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696724

show subpopulations

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:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000199

AC:

AN:

151012

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73738

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000443

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1614T>G (p.N538K) alteration is located in exon 15 (coding exon 15) of the EBF3 gene. This alteration results from a T to G substitution at nucleotide position 1614, causing the asparagine (N) at amino acid position 538 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

.;T

Eigen

Benign

-0.063

Eigen_PC

Benign

-0.068

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.061

B;.

Vest4

0.40

MutPred

0.21

Gain of ubiquitination at N538 (P = 0.0018);.;

MVP

0.41

MPC

0.94

ClinPred

0.80

GERP RS

3.1

Varity_R

0.21

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over