rs2298352

Positions:

• chr21-34880325-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.508+232A>G is an intronic variant with a MAF of 0.31559 (31.559%, 2745/8698, 11,443 alleles) in the African subpopulation of the gnomAD v.2 cohort is ≥ 0.0015 (0.15%) (BA1). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.537268 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) and splicing is not predicted to be impacted (BP4, 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, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA14879301/MONDO:0011071/008

• Frequency: Genomes: 𝑓 0.23 (4278 hom., cov: 33)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.513

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]

LOC112267915 (HGNC:):

RUNX1-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.508+232A>G		intron_variant		ENST00000675419.1	NP_001745.2
LOC112267915	XR_007067853.1	n.14093T>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.508+232A>G		intron_variant			NM_001754.5	ENSP00000501943	A1
RUNX1-AS1	ENST00000651798.1	n.662-3158T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34445 AN: 152054 Hom.: 4273 Cov.: 33

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0980

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.197

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

GnomAD4 genome AF: 0.227 AC: 34491 AN: 152172 Hom.: 4278 Cov.: 33 AF XY: 0.223 AC XY: 16597 AN XY: 74402

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.0982

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.197

Alfa AF: 0.213 Hom.: 1886

Bravo AF: 0.224

Asia WGS AF: 0.118 AC: 411 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Aug 28, 2024

NM_001754.5(RUNX1):c.508+232A>G is an intronic variant with a MAF of 0.31559 (31.559%, 2745/8698, 11,443 alleles) in the African subpopulation of the gnomAD v.2 cohort is ≥ 0.0015 (0.15%) (BA1). Evolutionary conservation algorithms predict the site as not being conserved (PhyloP score -0.537268 < 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species) and splicing is not predicted to be impacted (BP4, 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, BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2298352; hg19: chr21-36252622;