21-34981363-C-T

Variant names:

• chr21-34981363-C-T
• rs1981392
• NM_001754.5:c.58+67479G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001754.5(RUNX1):​c.58+67479G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 151,920 control chromosomes in the GnomAD database, including 26,008 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene RUNX1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.58 (26008 hom., cov: 31)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.524
• Publications: 3 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
• acute myeloid leukemia

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

ACMG classification

Specifications for RUNX1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.58+67479G>A		intron	N/A	NP_001745.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.58+67479G>A		intron	N/A	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.58+67479G>A		intron	N/A	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000416754.1	TSL:1	c.58+67479G>A		intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88560 AN: 151802 Hom.: 25964 Cov.: 31

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.590

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.584 AC: 88663 AN: 151920 Hom.: 26008 Cov.: 31 AF XY: 0.581 AC XY: 43143 AN XY: 74262

African (AFR) AF: 0.556 AC: 22995 AN: 41390

American (AMR) AF: 0.544 AC: 8306 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2259 AN: 3460

East Asian (EAS) AF: 0.687 AC: 3548 AN: 5166

South Asian (SAS) AF: 0.605 AC: 2916 AN: 4816

European-Finnish (FIN) AF: 0.538 AC: 5675 AN: 10558

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41065 AN: 67938

Other (OTH) AF: 0.589 AC: 1242 AN: 2108

Alfa AF: 0.595 Hom.: 57536

Bravo AF: 0.579

Asia WGS AF: 0.631 AC: 2197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.79
DANN	Benign	0.48
PhyloP100		-0.52

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: rs1981392; hg19: chr21-36353660;