21-34834635-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP4BP2

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.614-34C>T variant has a MAF of 1 (100%) in gnomAD cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state 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 summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014405/MONDO:0011071/008

Frequency

Genomes: 𝑓 1.0 ( 75579 hom., cov: 26)
Exomes 𝑓: 1.0 ( 487552 hom. )

Consequence

RUNX1
NM_001754.5 intron

Scores

2

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 1.07
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 -10 ACMG points.

BP2
BP4
BA1

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RUNX1NM_001754.5 linkuse as main transcriptc.614-34C>T intron_variant ENST00000675419.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RUNX1ENST00000675419.1 linkuse as main transcriptc.614-34C>T intron_variant NM_001754.5 A1Q01196-8

Frequencies

GnomAD3 genomes
AF:
1.00
AC:
151041
AN:
151042
Hom.:
75520
Cov.:
26
show subpopulations
Gnomad AFR
AF:
1.00
Gnomad AMI
AF:
1.00
Gnomad AMR
AF:
1.00
Gnomad ASJ
AF:
1.00
Gnomad EAS
AF:
1.00
Gnomad SAS
AF:
1.00
Gnomad FIN
AF:
1.00
Gnomad MID
AF:
1.00
Gnomad NFE
AF:
1.00
Gnomad OTH
AF:
1.00
GnomAD3 exomes
AF:
1.00
AC:
245506
AN:
245506
Hom.:
122753
AF XY:
1.00
AC XY:
133080
AN XY:
133080
show subpopulations
Gnomad AFR exome
AF:
1.00
Gnomad AMR exome
AF:
1.00
Gnomad ASJ exome
AF:
1.00
Gnomad EAS exome
AF:
1.00
Gnomad SAS exome
AF:
1.00
Gnomad FIN exome
AF:
1.00
Gnomad NFE exome
AF:
1.00
Gnomad OTH exome
AF:
1.00
GnomAD4 exome
AF:
0.999
AC:
975646
AN:
976190
Hom.:
487552
Cov.:
13
AF XY:
0.999
AC XY:
503815
AN XY:
504068
show subpopulations
Gnomad4 AFR exome
AF:
1.00
Gnomad4 AMR exome
AF:
1.00
Gnomad4 ASJ exome
AF:
1.00
Gnomad4 EAS exome
AF:
1.00
Gnomad4 SAS exome
AF:
1.00
Gnomad4 FIN exome
AF:
1.00
Gnomad4 NFE exome
AF:
0.999
Gnomad4 OTH exome
AF:
0.999
GnomAD4 genome
AF:
1.00
AC:
151159
AN:
151160
Hom.:
75579
Cov.:
26
AF XY:
1.00
AC XY:
73814
AN XY:
73814
show subpopulations
Gnomad4 AFR
AF:
1.00
Gnomad4 AMR
AF:
1.00
Gnomad4 ASJ
AF:
1.00
Gnomad4 EAS
AF:
1.00
Gnomad4 SAS
AF:
1.00
Gnomad4 FIN
AF:
1.00
Gnomad4 NFE
AF:
1.00
Gnomad4 OTH
AF:
1.00
Alfa
AF:
1.00
Hom.:
12066

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJun 22, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:2
Benign, reviewed by expert panelcurationClinGen Myeloid Malignancy Variant Curation Expert PanelJul 26, 2019The NM_001754.4:c.614-34C>T variant has a MAF of 1 (100%) in gnomAD cohort that is >/= 0.0015 (0.15%) (BA1). This variant is detected in homozygous state 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 summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 03, 2014- -
Acute myeloid leukemia Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
7.5
DANN
Benign
0.49
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.0

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

LitVar

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

Other links and lift over

dbSNP: rs11702841; hg19: chr21-36206932; API