21-34859476-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5_SupportingPP3PM2_SupportingPS4_ModeratePP1_StrongPM1

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

1

Splicing: ADA: 0.8271

1

1

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 7.90

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:

ENSG00000286153 (HGNC:56821): (RUNX1 antisense RNA 1)

ENSG00000286153 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.611G>A	p.Arg204Gln	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.611G>A	p.Arg204Gln	missense_variant, splice_region_variant	Exon 6 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Apr 13, 2018

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the germline of individuals with thrombocytopenia, myelodysplastic syndrome, acute myeloid leukemia, and/or acute lymphocytic leukemia in published literature (PMID: 27112265, 31130284, 32935436, 35739278); Published functional studies demonstrate a damaging effect: reduced DNA binding and transactivation (PMID: 10068652, 12393679); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R177Q; This variant is associated with the following publications: (PMID: 32782381, 31291480, 34166225, 32581362, 32935436, 31130284, 27112265, 19357396, 32208489, 26316320, 33778416, 34407276, 12393679, 27479822, 35739278, 36819173, 34958450, 37680325, Nitschke2023[article], 10068652) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Pathogenic:1

Mar 26, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Thrombocytopenia;C1458140:Abnormal bleeding

Pathogenic:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Thrombocytopenia

Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Pathogenic:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 204 of the RUNX1 protein (p.Arg204Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia or acute myeloid leukemia (PMID: 19357396, 27112265, 32208489, 32581362, 32935436). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg177Gln. ClinVar contains an entry for this variant (Variation ID: 561253). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 10068652, 11830488, 12002768, 22012064). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;D;D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

D

MutationAssessor

Uncertain

2.8

M;.;.;.;M;.

PrimateAI

Pathogenic

0.87

D

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;.

Polyphen

1.0

D;D;D;.;D;.

Vest4

0.93

MutPred

0.70

Gain of ubiquitination at K182 (P = 0.0177);.;.;Gain of ubiquitination at K182 (P = 0.0177);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

LitVar

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

Other links and lift over

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