rs76558016

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP2BP4BA1

This summary comes from the ClinGen Evidence Repository: This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least >5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although evolutionary conservation prediction algorithms predict the site as being moderately conserved (PhyloP score: 3.03 > 0.1 [-14.1;6.4]) and the variant is not the reference nucleotide in one primate and/or three mammal species, it 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, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA208646/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0041 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 9 hom. )

Consequence

RUNX1
NM_001754.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 2.88

Publications

6 publications found

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]

RUNX1 Gene-Disease associations (from GenCC):

hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

RUNX1 links:

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ACMG classification

Specifications for RUNX1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -10 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.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX1	NM_001754.5	MANE Select	c.183G>A	p.Pro61Pro	synonymous	Exon 4 of 9	NP_001745.2
RUNX1	NM_001001890.3		c.102G>A	p.Pro34Pro	synonymous	Exon 1 of 6	NP_001001890.1	Q01196-1
RUNX1	NM_001122607.2		c.102G>A	p.Pro34Pro	synonymous	Exon 1 of 5	NP_001116079.1	Q01196-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX1	ENST00000675419.1	MANE Select	c.183G>A	p.Pro61Pro	synonymous	Exon 4 of 9	ENSP00000501943.1	Q01196-8
RUNX1	ENST00000300305.7	TSL:1	c.183G>A	p.Pro61Pro	synonymous	Exon 3 of 8	ENSP00000300305.3	Q01196-8
RUNX1	ENST00000344691.8	TSL:1	c.102G>A	p.Pro34Pro	synonymous	Exon 1 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

629

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00105

AC:

242

AN:

230660

AF XY:

0.000850

show subpopulations

Gnomad AFR exome

AF:

0.0156

Gnomad AMR exome

AF:

0.000590

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000192

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.000398

AC:

578

AN:

1450550

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

244

AN XY:

721568

show subpopulations

African (AFR)

AF:

0.0147

AC:

491

AN:

33346

American (AMR)

AF:

0.000811

AC:

AN:

44392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25978

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

85988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45486

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000991

AC:

AN:

1109918

Other (OTH)

AF:

0.000649

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00413

AC:

629

AN:

152328

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0145

AC:

602

AN:

41564

American (AMR)

AF:

0.000980

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.00470

Asia WGS

AF:

0.00173

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)

Acute myeloid leukemia (1)

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

2.9

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over