21-35042790-T-C

Variant names:

• chr21-35042790-T-C
• rs7279123
• NM_001754.5:c.58+6052A>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+6052A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 152,152 control chromosomes in the GnomAD database, including 37,664 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 0.69 (37664 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 4 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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.58+6052A>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+6052A>G		intron_variant	Intron 2 of 8		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105379 AN: 152034 Hom.: 37647 Cov.: 32

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.725

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

GnomAD4 genome AF: 0.693 AC: 105440 AN: 152152 Hom.: 37664 Cov.: 32 AF XY: 0.698 AC XY: 51947 AN XY: 74410

African (AFR) AF: 0.511 AC: 21218 AN: 41484

American (AMR) AF: 0.761 AC: 11630 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2769 AN: 3468

East Asian (EAS) AF: 0.811 AC: 4203 AN: 5184

South Asian (SAS) AF: 0.869 AC: 4195 AN: 4828

European-Finnish (FIN) AF: 0.771 AC: 8167 AN: 10594

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50777 AN: 67996

Other (OTH) AF: 0.728 AC: 1539 AN: 2114

Alfa AF: 0.732 Hom.: 77496

Bravo AF: 0.682

Asia WGS AF: 0.831 AC: 2888 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	0.0090
DANN	Benign	0.19
PhyloP100		-1.4

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: rs7279123; hg19: chr21-36415087;