chr21-35553262-A-G

Variant names:

• chr21-35553262-A-G
• rs2834970
• ENST00000475045.6:c.-262+27398T>C

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-262+27398T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,022 control chromosomes in the GnomAD database, including 29,839 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 0.62 (29839 hom., cov: 32)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.563
• 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

LOC100506403 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC100506403	NR_073512.1	n.105+27398T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000475045.6	c.-262+27398T>C		intron_variant	Intron 8 of 12	5		ENSP00000477072.1
RUNX1	ENST00000467692.5	n.101+27398T>C		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94831 AN: 151904 Hom.: 29823 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.609

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

GnomAD4 genome AF: 0.624 AC: 94886 AN: 152022 Hom.: 29839 Cov.: 32 AF XY: 0.627 AC XY: 46610 AN XY: 74298

African (AFR) AF: 0.680 AC: 28196 AN: 41436

American (AMR) AF: 0.610 AC: 9332 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2208 AN: 3470

East Asian (EAS) AF: 0.827 AC: 4275 AN: 5170

South Asian (SAS) AF: 0.700 AC: 3376 AN: 4820

European-Finnish (FIN) AF: 0.605 AC: 6393 AN: 10562

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39171 AN: 67970

Other (OTH) AF: 0.609 AC: 1283 AN: 2106

Alfa AF: 0.617 Hom.: 4730

Bravo AF: 0.628

Asia WGS AF: 0.768 AC: 2674 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.7
DANN	Benign	0.40
PhyloP100		-0.56

Splicing

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

Other links and lift over

dbSNP: rs2834970; hg19: chr21-36925560;