21-34985055-T-C

Variant names:

• chr21-34985055-T-C
• rs2834714
• NM_001754.5:c.58+63787A>G

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+63787A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 151,926 control chromosomes in the GnomAD database, including 9,335 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.

• Frequency: Genomes: 𝑓 0.35 (9335 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.58+63787A>G		intron_variant	Intron 2 of 8	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.58+63787A>G		intron_variant	Intron 2 of 8		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53150 AN: 151808 Hom.: 9328 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.350 AC: 53200 AN: 151926 Hom.: 9335 Cov.: 32 AF XY: 0.348 AC XY: 25817 AN XY: 74236

African (AFR) AF: 0.331 AC: 13685 AN: 41402

American (AMR) AF: 0.301 AC: 4594 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3466

East Asian (EAS) AF: 0.409 AC: 2112 AN: 5170

South Asian (SAS) AF: 0.379 AC: 1831 AN: 4826

European-Finnish (FIN) AF: 0.329 AC: 3470 AN: 10538

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24774 AN: 67930

Other (OTH) AF: 0.358 AC: 755 AN: 2106

Alfa AF: 0.358 Hom.: 31362

Bravo AF: 0.345

Asia WGS AF: 0.422 AC: 1468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.11
DANN	Benign	0.43
PhyloP100		-1.5

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: rs2834714; hg19: chr21-36357352;