21-34792278-T-C

Variant names:

• chr21-34792278-T-C
• rs1555884837
• NM_001754.5:c.1300A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1300A>G (p.Asn434Asp) is a missense variant located in exon 9. This variant is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, which provide at least 20x coverage for the RUNX1 gene at this position (PM2_supporting). It has a REVEL score of 0.169 (≤0.50), and no evidence supports an impact on splicing, as indicated by a SpliceAI score of 0.00 (BP4). This variant has not been previously reported, and no pathogenic or likely pathogenic amino acid changes have been documented at the same residue. 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: PM2_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410147457/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 3.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1300A>G	p.Asn434Asp	missense_variant	Exon 9 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.1300A>G	p.Asn434Asp	missense_variant	Exon 9 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1388184 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 685286

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Uncertain:1

Jan 15, 2025

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.1300A>G (p.Asn434Asp) is a missense variant located in exon 9. This variant is absent from all population databases, including gnomAD v2.1.1 and gnomAD v3.1.2, which provide at least 20x coverage for the RUNX1 gene at this position (PM2_supporting). It has a REVEL score of 0.169 (≤0.50), and no evidence supports an impact on splicing, as indicated by a SpliceAI score of 0.00 (BP4). This variant has not been previously reported, and no pathogenic or likely pathogenic amino acid changes have been documented at the same residue. 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: PM2_supporting, BP4. -

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

Dec 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RUNX1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 sequence change replaces asparagine with aspartic acid at codon 434 of the RUNX1 protein (p.Asn434Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.020	D;D;D;D
Sift4G	Benign	0.42	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.13
MutPred		0.61		Gain of phosphorylation at T406 (P = 0.0999);.;.;.;
MVP		0.59
MPC		1.4
ClinPred		0.89	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.43

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: rs1555884837; hg19: chr21-36164575;