rs1555889947

Positions:

• chr21-34834471-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.744C>T (p.Asn248=) is a synonymous variant predicted by SSF and MES to lead to either an increase or a decrease in the canonical splice site score by no more than 10%, with no putative cryptic splice sites created (BP4). However, evolutionary conservation algorithms predict the site as being moderately conserved (PhyloP score: 2.55) and the variant is not the reference nucleotide in one primate and/or three mammal species. This variant is also absent from population databases (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512318594/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 31)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:1
• Conservation: PhyloP100: 3.99

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/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.744C>T	p.Asn248=	synonymous_variant	7/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.744C>T	p.Asn248=	synonymous_variant	7/9		NM_001754.5	ENSP00000501943	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Observed in an individual with familial platelet disorder (PMID: 34355501); This variant is associated with the following publications: (PMID: 34355501) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Oct 29, 2024

NM_001754.5(RUNX1):c.744C>T (p.Asn248=) is a synonymous variant predicted by SSF and MES to lead to either an increase or a decrease in the canonical splice site score by no more than 10%, with no putative cryptic splice sites created (BP4). However, evolutionary conservation algorithms predict the site as being moderately conserved (PhyloP score: 2.55) and the variant is not the reference nucleotide in one primate and/or three mammal species. This variant is also absent from population databases (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.91
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

Publications

LitVar

Other links and lift over

dbSNP: rs1555889947; hg19: chr21-36206768;