chr21-35538855-T-C

Variant names:

• chr21-35538855-T-C
• rs990074
• ENST00000475045.6:c.-262+41805A>G

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-262+41805A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 152,132 control chromosomes in the GnomAD database, including 34,892 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 0.67 (34892 hom., cov: 33)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 5 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

LOC100506403 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC100506403	NR_073512.1	n.105+41805A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000475045.6	c.-262+41805A>G		intron_variant	Intron 8 of 12	5		ENSP00000477072.1
RUNX1	ENST00000467692.5	n.101+41805A>G		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101767 AN: 152014 Hom.: 34858 Cov.: 33

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.657

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

GnomAD4 genome AF: 0.669 AC: 101850 AN: 152132 Hom.: 34892 Cov.: 33 AF XY: 0.671 AC XY: 49885 AN XY: 74350

African (AFR) AF: 0.820 AC: 34052 AN: 41514

American (AMR) AF: 0.633 AC: 9689 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2317 AN: 3466

East Asian (EAS) AF: 0.826 AC: 4275 AN: 5178

South Asian (SAS) AF: 0.702 AC: 3387 AN: 4828

European-Finnish (FIN) AF: 0.612 AC: 6463 AN: 10566

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39620 AN: 67970

Other (OTH) AF: 0.656 AC: 1385 AN: 2110

Alfa AF: 0.645 Hom.: 12285

Bravo AF: 0.679

Asia WGS AF: 0.787 AC: 2739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs990074; hg19: chr21-36911152;