Genetic Variant NM_001375380.1:c.983T>A (chr10-129867197-A-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_001375380.1(EBF3):c.983T>A(p.Leu328His) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L328F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

EBF3
NM_001375380.1 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.23

Publications

0 publications found

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:

EBF3-AS1 (HGNC:56218): (EBF3 antisense RNA 1)

EBF3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 10-129867197-A-T is Pathogenic according to our data. Variant chr10-129867197-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2536818.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375380.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EBF3	NM_001375380.1	MANE Select	c.983T>A	p.Leu328His	missense	Exon 10 of 17	NP_001362309.1	H0Y3W9
EBF3	NM_001375379.1		c.983T>A	p.Leu328His	missense	Exon 10 of 16	NP_001362308.1	Q9H4W6-1
EBF3	NM_001375389.1		c.983T>A	p.Leu328His	missense	Exon 10 of 17	NP_001362318.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EBF3	ENST00000440978.2	TSL:3 MANE Select	c.983T>A	p.Leu328His	missense	Exon 10 of 17	ENSP00000387543.2	H0Y3W9
EBF3	ENST00000368648.8	TSL:1	c.956T>A	p.Leu319His	missense	Exon 11 of 17	ENSP00000357637.3	Q9H4W6-2
EBF3	ENST00000904893.1		c.956T>A	p.Leu319His	missense	Exon 10 of 17	ENSP00000574952.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.6

PhyloP100

9.2

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.84

Gain of disorder (P = 0.0214)

MVP

0.96

MPC

2.7

ClinPred

1.0

GERP RS

4.9

Varity_R

0.92

gMVP

0.95

Mutation Taster

=8/92

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over