21-35979008-C-T

Variant names:

• chr21-35979008-C-T
• rs2835205
• ENST00000460207.1:n.344+2743G>A

Variant summary

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

The ENST00000460207.1(RUNX1):​n.344+2743G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0491 in 152,204 control chromosomes in the GnomAD database, including 265 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 0.049 (265 hom., cov: 32)
• Consequence: RUNX1 ENST00000460207.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• Publications: 0 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

LOC101928269 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000460207.1. 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
	LOC101928269	NR_110418.1		n.571+2743G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000460207.1	TSL:1	n.344+2743G>A		intron	N/A
	RUNX1	ENST00000475045.6	TSL:5	c.-864+2743G>A		intron	N/A	ENSP00000477072.1

Frequencies

GnomAD3 genomes AF: 0.0492 AC: 7482 AN: 152086 Hom.: 265 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0642

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0450

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

GnomAD4 genome AF: 0.0491 AC: 7478 AN: 152204 Hom.: 265 Cov.: 32 AF XY: 0.0484 AC XY: 3603 AN XY: 74406

African (AFR) AF: 0.0124 AC: 515 AN: 41550

American (AMR) AF: 0.0448 AC: 684 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3472

East Asian (EAS) AF: 0.00909 AC: 47 AN: 5170

South Asian (SAS) AF: 0.0552 AC: 266 AN: 4818

European-Finnish (FIN) AF: 0.0642 AC: 680 AN: 10588

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0720 AC: 4896 AN: 68008

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0231 Hom.: 59

Bravo AF: 0.0444

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.097
DANN	Benign	0.64
PhyloP100		-1.4

Splicing

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

Other links and lift over

dbSNP: rs2835205; hg19: chr21-37351306;