21-34788790-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2BA1

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.*3345A>T variant in the 3' UTR has an MAF of 0.09 (9%, 145/1560 alleles) in the East Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 16 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10652909/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0029 ( 26 hom., cov: 32)
Exomes 𝑓: 0.0077 ( 24 hom. )

Consequence

RUNX1
NM_001754.5 3_prime_UTR

Scores

2

Clinical Significance

Benign reviewed by expert panel B:2

Conservation

PhyloP100: 0.0770
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 -9 ACMG points.

BP2
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.*3345A>T 3_prime_UTR_variant 9/9 ENST00000675419.1 NP_001745.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RUNX1ENST00000675419.1 linkuse as main transcriptc.*3345A>T 3_prime_UTR_variant 9/9 NM_001754.5 ENSP00000501943 A1Q01196-8
RUNX1ENST00000300305.7 linkuse as main transcriptc.*3345A>T 3_prime_UTR_variant 8/81 ENSP00000300305 A1Q01196-8
RUNX1ENST00000344691.8 linkuse as main transcriptc.*3345A>T 3_prime_UTR_variant 6/61 ENSP00000340690 P4Q01196-1
RUNX1ENST00000437180.5 linkuse as main transcriptc.*3345A>T 3_prime_UTR_variant 9/95 ENSP00000409227 A1Q01196-8

Frequencies

GnomAD3 genomes
AF:
0.00293
AC:
446
AN:
152230
Hom.:
27
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.0770
Gnomad SAS
AF:
0.00331
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00143
GnomAD4 exome
AF:
0.00774
AC:
629
AN:
81262
Hom.:
24
Cov.:
0
AF XY:
0.00749
AC XY:
280
AN XY:
37404
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00117
Gnomad4 EAS exome
AF:
0.0531
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00296
GnomAD4 genome
AF:
0.00291
AC:
444
AN:
152348
Hom.:
26
Cov.:
32
AF XY:
0.00360
AC XY:
268
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000216
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.0768
Gnomad4 SAS
AF:
0.00331
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000555
Hom.:
1
Bravo
AF:
0.00350
Asia WGS
AF:
0.0220
AC:
77
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:2
Benign, reviewed by expert panelcurationClinGen Myeloid Malignancy Variant Curation Expert PanelJan 13, 2020The NM_001754.4:c.*3345A>T variant in the 3' UTR has an MAF of 0.09 (9%, 145/1560 alleles) in the East Asian subpopulation of the gnomAD v3 cohort and is =/> 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 16 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
9.6
DANN
Benign
0.78

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: rs56151547; hg19: chr21-36161087; API