21-34792178-G-T

Variant names:

• chr21-34792178-G-T
• rs1442794209
• NM_001754.5:c.1400C>A

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.1400C>A (p.Ala467Glu) is a missense variant which has a REVEL score ≤0.50 (0.09) and a SpliceAI score ≤ 0.20 (0.00) (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/CA410146806/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 0.859
• Publications: 4 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.

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.1400C>A	p.Ala467Glu	missense	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.1319C>A	p.Ala440Glu	missense	Exon 6 of 6	NP_001001890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.1400C>A	p.Ala467Glu	missense	Exon 9 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.1400C>A	p.Ala467Glu	missense	Exon 8 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.1319C>A	p.Ala440Glu	missense	Exon 6 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000758 AC: 1 AN: 131852 AF XY: 0.0000139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1378576 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 680314

African (AFR) AF: 0.00 AC: 0 AN: 31292

American (AMR) AF: 0.0000279 AC: 1 AN: 35790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24458

East Asian (EAS) AF: 0.00 AC: 0 AN: 36054

South Asian (SAS) AF: 0.00 AC: 0 AN: 77850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4594

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077584

Other (OTH) AF: 0.00 AC: 0 AN: 57470

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A467E variant (also known as c.1400C>A), located in coding exon 8 of the RUNX1 gene, results from a C to A substitution at nucleotide position 1400. The alanine at codon 467 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Uncertain:1

Jul 11, 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.1400C>A (p.Ala467Glu) is a missense variant which has a REVEL score ≤0.50 (0.09) and a SpliceAI score ≤ 0.20 (0.00) (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

Sep 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 463983). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 467 of the RUNX1 protein (p.Ala467Glu).

Acute myeloid leukemia Uncertain:1

Nov 23, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.86
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.085
Sift	Benign	0.15	T
Sift4G	Benign	0.31	T
Polyphen		0.99	D
Vest4		0.10
MutPred		0.66		Loss of glycosylation at T437 (P = 0.084)
MVP		0.38
MPC		1.1
ClinPred		0.17	T
GERP RS		1.4
Varity_R		0.14
gMVP		0.30
Mutation Taster		=85/15	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: rs1442794209; hg19: chr21-36164475;