chr21-35018644-G-T

Variant names:

• chr21-35018644-G-T
• rs2834736
• NM_001754.5:c.58+30198C>A

Variant summary

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

The NM_001754.5(RUNX1):​c.58+30198C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 152,038 control chromosomes in the GnomAD database, including 5,679 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. The gene RUNX1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.27 (5679 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 2 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Specifications for RUNX1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. 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
	RUNX1	NM_001754.5	MANE Select	c.58+30198C>A		intron	N/A	NP_001745.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.58+30198C>A		intron	N/A	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.58+30198C>A		intron	N/A	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000416754.1	TSL:1	c.58+30198C>A		intron	N/A	ENSP00000405158.1	A0A0C4DG58

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40542 AN: 151920 Hom.: 5676 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.267 AC: 40570 AN: 152038 Hom.: 5679 Cov.: 32 AF XY: 0.265 AC XY: 19676 AN XY: 74338

African (AFR) AF: 0.231 AC: 9591 AN: 41456

American (AMR) AF: 0.201 AC: 3071 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 641 AN: 3464

East Asian (EAS) AF: 0.202 AC: 1045 AN: 5170

South Asian (SAS) AF: 0.163 AC: 788 AN: 4822

European-Finnish (FIN) AF: 0.303 AC: 3203 AN: 10568

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21368 AN: 67962

Other (OTH) AF: 0.255 AC: 540 AN: 2114

Alfa AF: 0.284 Hom.: 3347

Bravo AF: 0.261

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.85
PhyloP100		0.070

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2834736; hg19: chr21-36390941;