rs1057519749

Positions:

• chr21-34880579-C-A
• chr21-34880579-C-G
• chr21-34880579-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5_Supporting PS1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.486G>T (p.Arg162Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3). This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376021, 376022) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>T variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376020) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, PS1_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602488/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 2.33

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.
• PP3: 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.486G>T	p.Arg162Ser	missense_variant	5/9	ENST00000675419.1	NP_001745.2
LOC112267915	XR_007067853.1	n.14347C>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.486G>T	p.Arg162Ser	missense_variant	5/9		NM_001754.5	ENSP00000501943	A1
RUNX1-AS1	ENST00000651798.1	n.662-2904C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jun 24, 2024

NM_001754.5(RUNX1):c.486G>T (p.Arg162Ser) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). REVEL score=0.818, which is >0.75 threshold. SSF and MES show loss of a putative cryptic donor splice site at c.485 (PP3). This variant is a missense change at the same residue (p.Arg162) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 376021, 376022) based on MM-VCEP rules for RUNX1 (PM5_Supporting). The c.486G>T variant is the same amino acid change (p.Arg162Ser) as a previously established likely pathogenic variant (ClinVar ID 376020) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PM5_supporting, PS1_moderate, PP3. -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.98
MutPred		0.81		Loss of methylation at R135 (P = 0.0118);.;.;Loss of methylation at R135 (P = 0.0118);Loss of methylation at R135 (P = 0.0118);.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96

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: rs1057519749; hg19: chr21-36252876; COSMIC: COSV100277991; COSMIC: COSV100277991;