21-34792240-G-C

Variant names:

• chr21-34792240-G-C
• rs769628054
• NM_001754.5:c.1338C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BP7 PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1338C>G (p.Leu446=) is a synonymous variant that is not predicted to impact splicing. Since it is a synonymous variant, no REVEL score is applicable, and SpliceAI is ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.004 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512341018/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.00900
• 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: Likely_benign. The variant received -1 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.
• BP7: 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.1338C>G	p.Leu446Leu	synonymous_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.1338C>G	p.Leu446Leu	synonymous_variant	Exon 9 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387770 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 685324

African (AFR) AF: 0.00 AC: 0 AN: 31806

American (AMR) AF: 0.00 AC: 0 AN: 36166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25074

East Asian (EAS) AF: 0.00 AC: 0 AN: 36230

South Asian (SAS) AF: 0.00 AC: 0 AN: 79458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080312

Other (OTH) AF: 0.00 AC: 0 AN: 57872

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Benign:1

Mar 28, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Jun 24, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.1338C>G (p.Leu446=) is a synonymous variant that is not predicted to impact splicing. Since it is a synonymous variant, no REVEL score is applicable, and SpliceAI is ≤ 0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score -0.004 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) (BP7). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM2_supporting.

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

Jun 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.6
DANN	Benign	0.71
PhyloP100		0.0090
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs769628054; hg19: chr21-36164537;