NM_001754.5:c.509-281G>T

Variant names:

• chr21-34859859-C-A
• rs2248720
• NM_001754.5:c.509-281G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP7 BP4 BP2 BA1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.509-281G>T is an intronic variant which has a MAF of 0.8530 (85.3%, 35321/41406, 35321 alleles) in the African/African American subpopulation of the gnomAD 3.1.2 cohort which is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 15115 individuals in a population database (gnomAD 3.1.2) (BP2). This intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.45) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA15984361/MONDO:0011071/008

• Frequency: Genomes: 𝑓 0.58 (28231 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.439
• Publications: 3 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: Benign. The variant received -11 ACMG points.

• BP2: 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.
• BA1: 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.509-281G>T		intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.428-281G>T		intron	N/A	NP_001001890.1
	RUNX1	NM_001122607.2		c.428-281G>T		intron	N/A	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.509-281G>T		intron	N/A	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.509-281G>T		intron	N/A	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.428-281G>T		intron	N/A	ENSP00000340690.4

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87737 AN: 151974 Hom.: 28198 Cov.: 32

Gnomad AFR AF: 0.853

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.567

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.577 AC: 87816 AN: 152092 Hom.: 28231 Cov.: 32 AF XY: 0.563 AC XY: 41864 AN XY: 74340

African (AFR) AF: 0.853 AC: 35430 AN: 41528

American (AMR) AF: 0.418 AC: 6383 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 1997 AN: 3470

East Asian (EAS) AF: 0.123 AC: 637 AN: 5172

South Asian (SAS) AF: 0.406 AC: 1955 AN: 4820

European-Finnish (FIN) AF: 0.418 AC: 4412 AN: 10554

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35215 AN: 67964

Other (OTH) AF: 0.563 AC: 1187 AN: 2110

Alfa AF: 0.557 Hom.: 24898

Bravo AF: 0.585

Asia WGS AF: 0.314 AC: 1098 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:1

Sep 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Jan 15, 2025

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.509-281G>T is an intronic variant which has a MAF of 0.8530 (85.3%, 35321/41406, 35321 alleles) in the African/African American subpopulation of the gnomAD 3.1.2 cohort which is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 15115 individuals in a population database (gnomAD 3.1.2) (BP2). This intronic variant has a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.0) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (-0.45) (BP7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2, BP4, BP7.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.17
DANN	Benign	0.31
PhyloP100		-0.44

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: rs2248720; hg19: chr21-36232156;