10-129841042-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001375380.1(EBF3):c.1373-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,509,798 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 22)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: EBF3 NM_001375380.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009954
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.329

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-129841042-T-C is Benign according to our data. Variant chr10-129841042-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3033969.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00173 (236/136128) while in subpopulation AFR AF= 0.00227 (87/38248). AF 95% confidence interval is 0.00189. There are 2 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High AC in GnomAd at 234 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EBF3	NM_001375380.1	c.1373-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000440978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EBF3	ENST00000440978.2	c.1373-10A>G		splice_polypyrimidine_tract_variant, intron_variant		3	NM_001375380.1
EBF3	ENST00000368648.8	c.1346-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1		A1
EBF3	ENST00000355311.10	c.1373-10A>G		splice_polypyrimidine_tract_variant, intron_variant		5		P4
EBF3	ENST00000675373.1	n.1018-10A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 234 AN: 136046 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00228

Gnomad AMI AF: 0.00360

Gnomad AMR AF: 0.00127

Gnomad ASJ AF: 0.000937

Gnomad EAS AF: 0.000885

Gnomad SAS AF: 0.000246

Gnomad FIN AF: 0.00223

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.00220

GnomAD3 exomes AF: 0.00269 AC: 365 AN: 135842 Hom.: 0 AF XY: 0.00288 AC XY: 207 AN XY: 71918

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00155

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00205

Gnomad SAS exome AF: 0.00264

Gnomad FIN exome AF: 0.00349

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000587 AC: 807 AN: 1373670 Hom.: 0 Cov.: 38 AF XY: 0.000663 AC XY: 448 AN XY: 675854

Gnomad4 AFR exome AF: 0.00169

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.000643

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.000975

Gnomad4 NFE exome AF: 0.000442

Gnomad4 OTH exome AF: 0.000509

GnomAD4 genome AF: 0.00173 AC: 236 AN: 136128 Hom.: 2 Cov.: 22 AF XY: 0.00157 AC XY: 102 AN XY: 64790

Gnomad4 AFR AF: 0.00227

Gnomad4 AMR AF: 0.00127

Gnomad4 ASJ AF: 0.000937

Gnomad4 EAS AF: 0.000888

Gnomad4 SAS AF: 0.000492

Gnomad4 FIN AF: 0.00223

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00218

Alfa AF: 0.000161 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EBF3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.39
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: rs866258379; hg19: chr10-131639306;