rs1057519748

Variant names:

• chr21-34859486-G-A
• rs1057519748
• NM_001754.5:c.601C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34859486-G-A
• chr21-34859486-G-C
• chr21-34859486-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1 PM2_Supporting PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.601C>T (p.Arg201Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMIDs: 10508512; 19387465; 20549580; 28513614). The variant was found to co-segregate with disease in multiple affected family members, with 14 meioses observed in across 4 families (PP1_Strong; PMID:10508512; 19387465; 20549580; 28513614). The variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4, PP1_Strong, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602487/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUNX1 NM_001754.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 4.54

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]

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

ACMG classification

Verdict is Pathogenic. Variant got 17 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.
• PP1: 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	c.601C>T	p.Arg201*	stop_gained	Exon 6 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.601C>T	p.Arg201*	stop_gained	Exon 6 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460898 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726862

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:3

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg201*) 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 acute myelogenous leukemia and/or familial thrombocytopenia (PMID: 10508512). ClinVar contains an entry for this variant (Variation ID: 376018). For these reasons, this variant has been classified as Pathogenic. -

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Apr 20, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RUNX1 gene demonstrated a sequence change, c.601C>T, which results in the creation of a premature stop codon at amino acid position 201, p.Arg201*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated RUNX1 protein with potentially abnormal function. This pathogenic sequence change is absent from population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple patients with RUNX1-related thrombocytopenia (Ripperger et al., 2009; Yoshima et al., 2016; Tawana et al., 2017). -

Sep 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); Also published as Arg174Ter; This variant is associated with the following publications: (PMID: 32477529, 26884589, 19387465, 28513614, 10508512, 20549580, 25525159, 25159113, 28102861, 31124578, 23848403, 30600763, 32554555) -

Inborn genetic diseases Pathogenic:1

Dec 20, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R201* pathogenic mutation (also known as c.601C>T), located in coding exon 5 of the RUNX1 gene, results from a C to T substitution at nucleotide position 601. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been reported in multiple individuals in the literature with a personal and/or family history of thrombocytopenia and/or hematologic malignancies (examples: Tawana K et al. Eur J Hum Genet. 2017 Aug;25(8):1020-1024; Ansar S et al. Genet Med. 2022 Nov;24(11):2367-2379; Liu C et al. EJHaem . 2023 Feb;4(1):145-152). In addition, this variant was reported to segregate with disease in multiple affected family members (Tawana K et al. Eur J Hum Genet. 2017 Aug;25(8):1020-1024; Liu C et al. EJHaem. 2023 Feb;4(1):145-152). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

RUNX1-related disorder Pathogenic:1

Feb 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RUNX1 c.601C>T variant is predicted to result in premature protein termination (p.Arg201*). This variant has been reported in several families with familial platelet disorder and hematologic malignancies (see for example Sood et al. 2017. PubMed ID: 28179279). Other RUNX1 gene variants that cause premature protein termination of the RUNX1 protein have been reported in numerous patients with thrombocytopenia and myeloid malignancies (Song et al. 1999. PubMed ID: 10508512; Buijs et al. 2012. PubMed ID: 22430633; Shiba et al. 2012. PubMed ID: 22138511). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in RUNX1 are expected to be pathogenic. In summary, the RUNX1 gene variant p.Arg201* is the type of variant expected to be a primary cause of disease and may also be associated with myeloid malignancy predisposition. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Sep 04, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001754.4:c.601C>T (p.Arg201Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMIDs: 10508512; 19387465; 20549580; 28513614). The variant was found to co-segregate with disease in multiple affected family members, with 14 meioses observed in across 4 families (PP1_Strong; PMID: 10508512; 19387465; 20549580; 28513614). The variant is absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4, PP1_Strong, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.91
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs1057519748; hg19: chr21-36231783; COSMIC: COSV55866784; COSMIC: COSV55866784;