chr21-34859476-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM5_SupportingPP3PM2_SupportingPS4_ModeratePP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.611G>A (p.Arg204Gln) variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.958) (PP3). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ moderate; PMID:19357396, PMID:27112265, PMID:26316320, PMID:27479822). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families (PP1_strong; PMID:19357396, PMID:27112265, PMID:26316320, PMID:27479822). This variant is a missense change at the same residue (p.R204) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 2177591) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_strong, PM1, PM2, PS4_moderate, PP3, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410207938/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense, splice_region

Scores

13

5

Splicing: ADA: 0.8271

1

1

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 7.90

Publications

2 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 links:

RUNX1-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

RUNX1-AS1 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: Pathogenic. The variant received 11 ACMG points.

PS4

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

PM1

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

PM2

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

PM5

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

PP1

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

PP3

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.611G>A	p.Arg204Gln	missense splice_region	Exon 6 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.530G>A	p.Arg177Gln	missense splice_region	Exon 3 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.530G>A	p.Arg177Gln	missense splice_region	Exon 3 of 5	NP_001116079.1	Q01196-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.611G>A	p.Arg204Gln	missense splice_region	Exon 6 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.611G>A	p.Arg204Gln	missense splice_region	Exon 5 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.530G>A	p.Arg177Gln	missense splice_region	Exon 3 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152100

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

1

AN:

1458178

Hom.:

0

Cov.:

30

AF XY:

0.00000138

AC XY:

1

AN XY:

725764

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33382

American (AMR)

AF:

0.00

AC:

0

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5764

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

1

AN:

1108678

Other (OTH)

AF:

0.00

AC:

0

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<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:

0.00000657

AC:

1

AN:

152100

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74294

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

0

AN:

41416

American (AMR)

AF:

0.0000654

AC:

1

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68004

Other (OTH)

AF:

0.00

AC:

0

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

0

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

3

-

-

not provided (3)

2

-

-

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

1

-

-

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)

1

-

-

Inborn genetic diseases (1)

1

-

-

Thrombocytopenia (1)

1

-

-

Thrombocytopenia;C1458140:Abnormal bleeding (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

34

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.94

D

LIST_S2

Pathogenic

1.0

D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.91

D

MetaSVM

Pathogenic

0.99

D

MutationAssessor

Uncertain

2.8

M

PhyloP100

7.9

PrimateAI

Pathogenic

0.87

D

PROVEAN

Uncertain

-3.7

D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D

Sift4G

Uncertain

0.0020

D

Polyphen

1.0

D

Vest4

0.93

MutPred

0.70

Gain of ubiquitination at K182 (P = 0.0177)

MVP

1.0

MPC

1.6

ClinPred

1.0

D

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Pathogenic

0.76

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

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Other links and lift over

dbSNP: rs1569061762; hg19: chr21-36231773; COSMIC: COSV55866469; COSMIC: COSV55866469; API