chr21-34880714-C-A

Position:

• chr21-34880714-C-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP1_Strong PVS1 PM2 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.352-1G>T variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1; PMID:10508512). This variant was found to co-segregate with disease in multiple affected family members, with more than seven meioses (at least 25 affected individuals) observed in one family/across X families (PP1_Strong; 10508512). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID:11830488). 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, PP1_Strong, PM2, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248609/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUNX1 NM_001754.5 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 15 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.
• PP1: 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.352-1G>T		splice_acceptor_variant		ENST00000675419.1	NP_001745.2
LOC112267915	XR_007067853.1	n.14482C>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.352-1G>T		splice_acceptor_variant			NM_001754.5	ENSP00000501943	A1
RUNX1-AS1	ENST00000651798.1	n.662-2769C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Aug 01, 2019	The NM_001754.4:c.352-1G>T variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1; PMID: 10508512). This variant was found to co-segregate with disease in multiple affected family members, with more than seven meioses (at least 25 affected individuals) observed in one family/across X families (PP1_Strong; 10508512). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). 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, PP1_Strong, PM2, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 21, 2022	Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 10508512). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 14463). This sequence change affects an acceptor 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial thrombocytopenia (PMID: 10508512). It has also been observed to segregate with disease in related individuals. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
GERP RS		5.3
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	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -14
DS_AL_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: rs587776809; hg19: chr21-36253011; COSMIC: COSV55890980;