chr21-35050181-C-T

Variant names:

• chr21-35050181-C-T
• rs2071029
• ENST00000475045.6:c.-59-1223G>A

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-59-1223G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,048 control chromosomes in the GnomAD database, including 4,372 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 0.22 (4372 hom., cov: 32)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.213
• 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=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 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.-59-1223G>A		intron_variant	Intron 10 of 12	5		ENSP00000477072.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33444 AN: 151930 Hom.: 4371 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.206

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

GnomAD4 genome AF: 0.220 AC: 33493 AN: 152048 Hom.: 4372 Cov.: 32 AF XY: 0.219 AC XY: 16303 AN XY: 74318

African (AFR) AF: 0.359 AC: 14868 AN: 41432

American (AMR) AF: 0.225 AC: 3437 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 532 AN: 3472

East Asian (EAS) AF: 0.333 AC: 1722 AN: 5166

South Asian (SAS) AF: 0.149 AC: 719 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1567 AN: 10570

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10024 AN: 67990

Other (OTH) AF: 0.208 AC: 439 AN: 2112

Alfa AF: 0.175 Hom.: 4077

Bravo AF: 0.234

Asia WGS AF: 0.242 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.7
DANN	Benign	0.78
PhyloP100		0.21

Splicing

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

Other links and lift over

dbSNP: rs2071029; hg19: chr21-36422478; COSMIC: COSV55883511;