chr21-34880663-A-G

Variant names:

• chr21-34880663-A-G
• rs1555898635
• NM_001754.5:c.402T>C

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: This c.402T>C (p.Ala134=) synonymous variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP score = -2.40196 in GRCh38); it is not predicted to have any splicing impact per SpliceAI (BP7+BP4). The variant is absent from population databases, including gnomAD v2 and v3 (PM2_supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1 (version 2): BP4, BP7, and PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512318752/MONDO:0011071/008

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:2
• Conservation: PhyloP100: -2.35
• Publications: 0 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-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

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.402T>C	p.Ala134Ala	synonymous	Exon 5 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.321T>C	p.Ala107Ala	synonymous	Exon 2 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.321T>C	p.Ala107Ala	synonymous	Exon 2 of 5	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.402T>C	p.Ala134Ala	synonymous	Exon 5 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.402T>C	p.Ala134Ala	synonymous	Exon 4 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.321T>C	p.Ala107Ala	synonymous	Exon 2 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.58
DANN	Benign	0.52
PhyloP100		-2.4

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: rs1555898635; hg19: chr21-36252960;