21-34880581-T-C

Variant names:

• chr21-34880581-T-C
• rs1057519751
• NM_001754.5:c.484A>G

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5_Supporting PP3 PP1 PS3_Moderate PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.484A>G variant in RUNX1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 162 (p.R162G), which is a residue that directly contacts DNA (PMID:11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID:31648317, 27294619, 23958918), especially from a somatic perspective (PMID:32208489) (PM1). This variant is absent from gnomAD v2 and v3 (PM2_Supporting), and has been reported in a proband meeting RUNX1-phenotypic criteria: history of bruising, menorrhagia, anemia, and a platelet defect with atypical platelet function tests, abnormal electron microscopy study, and atypical macrophages on bone marrow biopsy (PS4_Supporting; SCV001375396.1 and National Human Genome Research Institute). In addition, her older son (non-carrier) is unaffected, her younger son (carrier) has a history of thrombocytopenia (easy bleeding and bruising), frequent epistaxis, petechiae at 9 months, and an abnormal platelet electron microscopy study, and her mother (carrier) was diagnosed with AML at 45 (BMT done) and has a history of easy bleeding (PP1; National Human Genome Research Institute); finally, there is a supportive family history of AML in deceased relatives. Note that all other reports of the variant are not clearly germline (PMID:19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). Functionally, the variant demonstrates reduced DNA-binding and CBFβ-binding (PMID:17290219), as well as impaired erythropoiesis (PMID:17234761, 21725049 (PS3_Moderate), which is in line with computational evidence (REVEL score of 0.885 ≥ 0.88 threshold; PP3). 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: PS3_Moderate, PS4_Supporting, PM1, PM2_Supporting, PP1, and PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602491/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1 U:3
• Conservation: PhyloP100: 1.84
• Publications: 21 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.484A>G	p.Arg162Gly	missense	Exon 5 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.403A>G	p.Arg135Gly	missense	Exon 2 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.403A>G	p.Arg135Gly	missense	Exon 2 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.484A>G	p.Arg162Gly	missense	Exon 5 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.484A>G	p.Arg162Gly	missense	Exon 4 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.403A>G	p.Arg135Gly	missense	Exon 2 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

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 c.484A>G variant in RUNX1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 162 (p.R162G), which is a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) (PM1). This variant is absent from gnomAD v2 and v3 (PM2_Supporting), and has been reported in a proband meeting RUNX1-phenotypic criteria: history of bruising, menorrhagia, anemia, and a platelet defect with atypical platelet function tests, abnormal electron microscopy study, and atypical macrophages on bone marrow biopsy (PS4_Supporting; SCV001375396.1 and National Human Genome Research Institute). In addition, her older son (non-carrier) is unaffected, her younger son (carrier) has a history of thrombocytopenia (easy bleeding and bruising), frequent epistaxis, petechiae at 9 months, and an abnormal platelet electron microscopy study, and her mother (carrier) was diagnosed with AML at 45 (BMT done) and has a history of easy bleeding (PP1; National Human Genome Research Institute); finally, there is a supportive family history of AML in deceased relatives. Note that all other reports of the variant are not clearly germline (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 30373888, 31649132, 32045476, 32208489). Functionally, the variant demonstrates reduced DNA-binding and CBFβ-binding (PMID: 17290219), as well as impaired erythropoiesis (PMID: 17234761, 21725049 (PS3_Moderate), which is in line with computational evidence (REVEL score of 0.885 ≥ 0.88 threshold; PP3). 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: PS3_Moderate, PS4_Supporting, PM1, PM2_Supporting, PP1, and PP3.

Inborn genetic diseases Uncertain:1

Mar 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R162G variant (also known as c.484A>G), located in coding exon 4 of the RUNX1 gene, results from an A to G substitution at nucleotide position 484. The arginine at codon 162 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Abnormal platelet function Uncertain:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1

Jun 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 162 of the RUNX1 protein (p.Arg162Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RUNX1-related conditions (PMID: 31064749). This variant is also known as p.R135G. ClinVar contains an entry for this variant (Variation ID: 376022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RUNX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 12807882, 17234761, 24523240). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.78		Loss of methylation at R135 (P = 0.0118)
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519751; hg19: chr21-36252878; COSMIC: COSV55867213; COSMIC: COSV55867213;