chr21-34880581-T-C

Position:

• chr21-34880581-T-C

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PP1 PS3_Moderate PM2_Supporting PS4_Supporting PM1 PM5_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:2
• Conservation: PhyloP100: 1.84

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.484A>G	p.Arg162Gly	missense_variant	5/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.484A>G	p.Arg162Gly	missense_variant	5/9		NM_001754.5	ENSP00000501943.1

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

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 Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Mar 26, 2024

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. -

Abnormal platelet function Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2019

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. This variant has been reported to affect RUNX1 protein function (PMID: 12807882, 17234761, 24523240). This variant is also known as p.R135G in the literature. This variant has not been reported in the literature in individuals with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 376022). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 162 of the RUNX1 protein (p.Arg162Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.98
MutPred		0.78		Loss of methylation at R135 (P = 0.0118);.;.;Loss of methylation at R135 (P = 0.0118);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

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