21-34880580-C-T

Variant names:

• chr21-34880580-C-T
• rs1057519750
• NM_001754.5:c.485G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.485G>A (p.Arg162Lys) is a missense variant which affects one of the following hotspot residues within the RHD: R162 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This missense variant has a REVEL score of 0.949 (PP3). 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: PM1, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602490/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:2 O:2
• Conservation: PhyloP100: 7.57
• Publications: 25 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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 rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.485G>A	p.Arg162Lys	missense_variant	Exon 5 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.485G>A	p.Arg162Lys	missense_variant	Exon 5 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

⚠️ 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: 39694

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:2 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Acute myeloid leukemia Uncertain:1 Other:2

Aug 23, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.485G>A commonly occurs as a somatic variant in association with RUNX1-related disease6, but it has not been reported to occur as a germline variant causative of RUNX1-related disease in the literature, to our knowledge. It is absent from a large population dataset , and has been reported in ClinVar (Variation ID 376021). Two bioinformatic tools queried predict that this substitution would be damaging, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The arginine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.485G>A in RUNX1 to be uncertain at this time. -

Jan 24, 2024

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. It was classified likely pathogenic in Hereditary Thrombocytopenia and Hematologic Cancer Predisposition Syndrome by a ClinGen expert panel. -

Jan 24, 2024

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. AML patients harboring RUNX1 mutations, in the absence of other favorable risk markers, have been placed in the poor/adverse risk category by the 2017 European LeukemiaNet recommendations for AML, which are cited in the NCCN Guidelines (v.1.2022) (Döhner et al., 2017;27895058). -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Jan 12, 2021

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant by SCV001203102.1 in a proband (70s) with thrombocytopenia and anemia; however, the germline origins were not confirmed in this case and all other reports of the variant (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 28933735, 30373888, 31649132, 32045476, 32208489, COSMIC). The variant is located at 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]. Although this variant has not been functionally evaluated, computational evidence supports a deleterious effect of this variant [PP3] and another missense variant at the same residue (i.e. p.R162G) is classified as likely pathogenic by the ClinGen MM-VCEP [PM5_supporting]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2, PM5_supporting, and PP3. -

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

Jul 27, 2023

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 lysine, which is basic and polar, at codon 162 of the RUNX1 protein (p.Arg162Lys). 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. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 25840971). 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. ClinVar contains an entry for this variant (Variation ID: 376021). This variant is also known as 404G>A, Arg135Lys. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;.
Polyphen		0.99	D;D;D;.;P;.
Vest4		0.95
MutPred		0.82		Loss of methylation at R135 (P = 0.047);.;.;Loss of methylation at R135 (P = 0.047);Loss of methylation at R135 (P = 0.047);.;
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.93
Mutation Taster		=25/75	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: rs1057519750; hg19: chr21-36252877; COSMIC: COSV55868310; COSMIC: COSV55868310;