rs1060502579

Variant names:

• chr21-34886842-C-A
• rs1060502579
• NM_001754.5:c.351+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34886842-C-A
• chr21-34886842-C-G
• chr21-34886842-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1). This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID:24100448 and 32935436). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_moderate, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410203333/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.39

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.351+1G>T		splice_donor_variant, intron_variant	Intron 4 of 8	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.351+1G>T		splice_donor_variant, intron_variant	Intron 4 of 8		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Dec 09, 2023

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. The c.351+1G>T variant is a canonical splice site variant predicted to disrupt exon 4 donor splice site recognition. According to SpliceAI prediction, the donor loss is 0.99 at -1 bp. This variant is expected to result in exon 4 skipping, leading to a frameshift (PVS1). This variant has been reported in 2 probands (#17, and #44.2), both meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 24100448 and 32935436). This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and gnomAD v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_moderate, PM2_supporting. -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502579; hg19: chr21-36259139; COSMIC: COSV55897469; COSMIC: COSV55897469;