chr21-35068403-T-A

Variant names:

• chr21-35068403-T-A
• rs10483024
• ENST00000475045.6:c.-196-3331A>T

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-196-3331A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,174 control chromosomes in the GnomAD database, including 2,939 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 0.19 (2939 hom., cov: 32)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275
• Publications: 1 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000475045.6	c.-196-3331A>T		intron_variant	Intron 9 of 12	5		ENSP00000477072.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29485 AN: 152056 Hom.: 2936 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.193

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

GnomAD4 genome AF: 0.194 AC: 29515 AN: 152174 Hom.: 2939 Cov.: 32 AF XY: 0.195 AC XY: 14502 AN XY: 74386

African (AFR) AF: 0.168 AC: 6957 AN: 41524

American (AMR) AF: 0.236 AC: 3608 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 609 AN: 3472

East Asian (EAS) AF: 0.343 AC: 1774 AN: 5174

South Asian (SAS) AF: 0.152 AC: 735 AN: 4826

European-Finnish (FIN) AF: 0.202 AC: 2136 AN: 10592

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13155 AN: 67982

Other (OTH) AF: 0.195 AC: 411 AN: 2112

Alfa AF: 0.105 Hom.: 161

Bravo AF: 0.197

Asia WGS AF: 0.239 AC: 831 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.4
DANN	Benign	0.45
PhyloP100		0.28

Splicing

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

Other links and lift over

dbSNP: rs10483024; hg19: chr21-36440700;