rs759068561

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PS4_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter) is a nonsense variant that is predicted to undergo NMD (PVS1, SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID:27210295). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CV1459069/MONDO:0011071/008

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 2.68

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:

LOC112267915 (HGNC:):

LOC112267915 links:

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

RUNX1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

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

PS4

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

PM2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.496C>T	p.Arg166Ter	stop_gained	5/9	ENST00000675419.1	NP_001745.2
LOC112267915	XR_007067853.1 linkuse as main transcript	n.14337G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.496C>T	p.Arg166Ter	stop_gained	5/9		NM_001754.5	ENSP00000501943	A1	Q01196-8
RUNX1-AS1	ENST00000651798.1 linkuse as main transcript	n.662-2914G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727188

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Pathogenic:2

Pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This sequence change creates a premature translational stop signal (p.Arg166*) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with features of RUNX1-related conditions (PMID: 21725049, 26525156, 28659335). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R139X. ClinVar contains an entry for this variant (Variation ID: 1459069). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals with familial platelet disorder/acute myeloid leukemia, and found to segregate with disease in multiple affected individuals from several families as well as occur de novo with confirmed parentage in patients tested at GeneDx and in published literature (Haslam 2016, Latger-Cannard 2016, Kanagal-Shamanna 2017); Published functional studies demonstrate defective hematopoiesis (Bluteau 2011, Bluteau 2012); Not observed in large population cohorts (gnomAD); Also known as p.Arg139Ter; This variant is associated with the following publications: (PMID: 26525156, 27112265, 28659335, 21725049, 22898599, 31124578, 33351114, 32315381) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Apr 25, 2022

NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter) is a nonsense variant that is predicted to undergo NMD (PVS1, SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27210295). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.86

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

Vest4

0.93

GERP RS

2.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over