rs186585782

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BA1BP4BP2BP7

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.613+8C>T variant has a MAF of 0.00151 (0.151%, 101/66,722 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (15) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.2534 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014475/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0028 ( 13 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 30 hom. )

Consequence

RUNX1
NM_001754.5 splice_region, intron

Scores

2
Splicing: ADA: 0.00003648
2

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -1.22
Variant links:
Genes affected
RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP2
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.
BP7
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RUNX1NM_001754.5 linkuse as main transcriptc.613+8C>T splice_region_variant, intron_variant ENST00000675419.1 NP_001745.2 Q01196-8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RUNX1ENST00000675419.1 linkuse as main transcriptc.613+8C>T splice_region_variant, intron_variant NM_001754.5 ENSP00000501943.1 Q01196-8

Frequencies

GnomAD3 genomes
AF:
0.00283
AC:
430
AN:
152182
Hom.:
13
Cov.:
33
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:
0.0341
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000941
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00321
AC:
806
AN:
251468
Hom.:
9
AF XY:
0.00286
AC XY:
389
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.0322
Gnomad NFE exome
AF:
0.000844
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00135
AC:
1950
AN:
1439376
Hom.:
30
Cov.:
28
AF XY:
0.00130
AC XY:
934
AN XY:
717534
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000699
Gnomad4 FIN exome
AF:
0.0309
Gnomad4 NFE exome
AF:
0.000214
Gnomad4 OTH exome
AF:
0.000973
GnomAD4 genome
AF:
0.00282
AC:
430
AN:
152300
Hom.:
13
Cov.:
33
AF XY:
0.00414
AC XY:
308
AN XY:
74474
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:
0.0341
Gnomad4 NFE
AF:
0.000941
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00116
Hom.:
0
Bravo
AF:
0.000136
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 01, 2024- -
Benign, reviewed by expert panelcurationClinGen Myeloid Malignancy Variant Curation Expert PanelAug 02, 2019The NM_001754.4:c.613+8C>T variant has a MAF of 0.00151 (0.151%, 101/66,722 alleles) in the European (Non-Finnish) subpopulation of the ExAC cohort that is >/= 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (15) in gnomAD population database (BP2). This intronic variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). In addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -1.2534 < 0.1) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 11, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.45
DANN
Benign
0.41
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000036
dbscSNV1_RF
Benign
0.0
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

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

Other links and lift over

dbSNP: rs186585782; hg19: chr21-36231763; API