rs1057519522

Variant names:

• chr10-129877788-G-A
• rs1057519522
• NM_001375380.1:c.616C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001375380.1(EBF3):​c.616C>T​(p.Arg206*) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EBF3 NM_001375380.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.66
• Publications: 7 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-129877788-G-A is Pathogenic according to our data. Variant chr10-129877788-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 375503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBF3	NM_001375380.1	MANE Select	c.616C>T	p.Arg206*	stop_gained	Exon 7 of 17	NP_001362309.1	H0Y3W9
	EBF3	NM_001375379.1		c.616C>T	p.Arg206*	stop_gained	Exon 7 of 16	NP_001362308.1	Q9H4W6-1
	EBF3	NM_001375389.1		c.616C>T	p.Arg206*	stop_gained	Exon 7 of 17	NP_001362318.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBF3	ENST00000440978.2	TSL:3 MANE Select	c.616C>T	p.Arg206*	stop_gained	Exon 7 of 17	ENSP00000387543.2	H0Y3W9
	EBF3	ENST00000368648.8	TSL:1	c.616C>T	p.Arg206*	stop_gained	Exon 8 of 17	ENSP00000357637.3	Q9H4W6-2
	EBF3	ENST00000904893.1		c.616C>T	p.Arg206*	stop_gained	Exon 7 of 17	ENSP00000574952.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hypotonia, ataxia, and delayed development syndrome (3)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.7
Vest4		0.74
GERP RS		5.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1057519522; hg19: chr10-131676052; COSMIC: COSV100799313;