21-34886975-G-C

Variant names:

• chr21-34886975-G-C
• rs1157495777
• NM_001754.5:c.219C>G

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.219C>G (p.Ser73Arg) is a missense variant which has a REVEL score < 0.50 (0.411) and a SpliceAI score ≤ 0.20 (0.03) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410203871/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 1.37
• Publications: 0 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 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP4: 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.219C>G	p.Ser73Arg	missense_variant	Exon 4 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.219C>G	p.Ser73Arg	missense_variant	Exon 4 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457112 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724980

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110980

Other (OTH) AF: 0.00 AC: 0 AN: 60264

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S73R variant (also known as c.219C>G), located in coding exon 3 of the RUNX1 gene, results from a C to G substitution at nucleotide position 219. The serine at codon 73 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Uncertain:1

Nov 13, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.219C>G (p.Ser73Arg) is a missense variant which has a REVEL score < 0.50 (0.411) and a SpliceAI score ≤ 0.20 (0.03) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4. -

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

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 73 of the RUNX1 protein (p.Ser73Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1037898). 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 not expected to disrupt RUNX1 protein function with a negative predictive value of 80%. 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.48	T;.;.;.;.;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.75	T;D;.;T;T;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	0.55	N;.;.;.;N;.;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.26	T;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;.;T
Polyphen		0.39	B;P;P;.;B;.;.
Vest4		0.40
MutPred		0.19		Gain of MoRF binding (P = 0.0186);.;.;Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);.;.;
MVP		0.83
MPC		1.1
ClinPred		0.85	D
GERP RS		-1.1
PromoterAI		-0.025	Neutral
Varity_R		0.21
gMVP		0.32
Mutation Taster		=62/38	polymorphism

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: rs1157495777; hg19: chr21-36259272;