21-34886842-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5_Supporting PVS1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID:27931139). 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, PM2_supporting, PS4_Supporting, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410203336/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:5
• 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 12 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.
• PM5: 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>A		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>A		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:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Sep 03, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RUNX1 gene demonstrated a sequence change in the canonical splice donor site of intron 4, c.351+1G>A. This pathogenic sequence change is predicted to affect normal splicing of the RUNX1 gene and result in an abnormal protein which may be degraded, or may lead to the production of a truncated RUNX1 protein with potentially abnormal function. This pathogenic sequence change is absent from population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple patients with RUNX1-related thrombocytopenia (PMIDs:18723428, 28240786, 28102861, 28485484, 27931139). This sequence change is the likely cause of this disease phenotype, however functional studies have not been performed to prove this conclusively. -

Mar 28, 2017

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Mar 26, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.351+1G>A is a splice donor variant that is predicted to introduce exon 4 skipping and a frameshift with a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27931139). 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, PM2_supporting, PS4_Supporting, PM5_supporting. -

Thrombocytopenia Pathogenic:1

Jan 20, 2021

Bone Marrow Failure laboratory, Queen Mary University London

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This heterozygous, splice variant of RUNX1 was identified in a female with thrombocytopenia, aged 39years (PMID:18723428). Her mother died of CMML (with 11q23 abnormality), maternal uncle died of leukaemia age 64 yrs and maternal cousin had thrombocytopenia and died of AML aged 23 yrs but these individuals were not tested for the variant. The following ACMG/AMP criteria were used: PVS1, PM2 and PP3. -

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

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 561236). This variant is also known as splice donor site mutation in intron 3. Disruption of this splice site has been observed in individual(s) with clinical features of RUNX1-related conditions (PMID: 18723428, 27931139, 28102861, 28240786). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the RUNX1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.96	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;