21-34886900-G-C

Variant names:

• chr21-34886900-G-C
• rs1368531129
• NM_001754.5:c.294C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BP7 PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The c.294C>G (p.Leu98=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being not highly conserved (PhyloP score = 1.16043 in GRCh38) (BP7). Although the variant is absent from from gnomAD v2 and v3 (PM2_Supporting), it also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512318850/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.19
• Publications: 1 publications found

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]

RUNX1 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.294C>G	p.Leu98Leu	synonymous	Exon 4 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.213C>G	p.Leu71Leu	synonymous	Exon 1 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.213C>G	p.Leu71Leu	synonymous	Exon 1 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.294C>G	p.Leu98Leu	synonymous	Exon 4 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.294C>G	p.Leu98Leu	synonymous	Exon 3 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.213C>G	p.Leu71Leu	synonymous	Exon 1 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Benign:1

Nov 25, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Nov 13, 2023

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.294C>G (p.Leu98=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being not highly conserved (PhyloP score = 1.16043 in GRCh38) (BP7). Although the variant is absent from from gnomAD v2 and v3 (PM2_Supporting), it also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4, BP7, and PM2_Supporting.

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

Dec 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		1.2
PromoterAI		0.035	Neutral

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

Other links and lift over

dbSNP: rs1368531129; hg19: chr21-36259197;