rs1555899712

Positions:

• chr21-34886838-A-G
• chr21-34886838-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. BP4 PM2_Supporting BP7

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.351+5T>C is an intronic variant has spliceAI ∆ scores ≤ 0.20 (BP4)Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score (0.3) < 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: PM2_supporting, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658656804/MONDO:0100083/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0002134
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: 0.428

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 Likely_benign. Variant got -1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.351+5T>C		splice_donor_5th_base_variant, intron_variant		ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.351+5T>C		splice_donor_5th_base_variant, intron_variant			NM_001754.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Aug 23, 2022	NM_001754.5(RUNX1):c.351+5T>C is an intronic variant has spliceAI ∆ scores <= 0.20 (BP4)Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score (0.3) < 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: PM2_supporting, BP4, BP7. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	This sequence change falls in intron 4 of the RUNX1 gene. It does not directly change the encoded amino acid sequence of the RUNX1 protein. It affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 463992). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.020
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: rs1555899712; hg19: chr21-36259135;