21-34792108-G-T

Variant names:

• chr21-34792108-G-T
• rs13051066
• NM_001754.5:c.*27C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BP2

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.*27C>A variant in the 3' UTR has an MAF of 0.4444 (44%, 1352/3042 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 301 individuals in the gnomAD v3 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014168/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.37 (10586 hom., cov: 31)
  • Exomes 𝑓: 0.43 (109377 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.391
• Publications: 11 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

Our verdict: Benign. The variant received -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.*27C>A		3_prime_UTR	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.*27C>A		3_prime_UTR	Exon 6 of 6	NP_001001890.1	Q01196-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.*27C>A		3_prime_UTR	Exon 9 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.*27C>A		3_prime_UTR	Exon 8 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.*27C>A		3_prime_UTR	Exon 6 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55035 AN: 150170 Hom.: 10588 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.364

GnomAD2 exomes AF: 0.485 AC: 3719 AN: 7666 AF XY: 0.486

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.403

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.531

GnomAD4 exome AF: 0.427 AC: 505328 AN: 1183120 Hom.: 109377 Cov.: 23 AF XY: 0.428 AC XY: 245121 AN XY: 573334

African (AFR) AF: 0.224 AC: 5113 AN: 22846

American (AMR) AF: 0.381 AC: 3836 AN: 10058

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 6391 AN: 16166

East Asian (EAS) AF: 0.377 AC: 10233 AN: 27136

South Asian (SAS) AF: 0.453 AC: 22598 AN: 49880

European-Finnish (FIN) AF: 0.468 AC: 13227 AN: 28266

Middle Eastern (MID) AF: 0.349 AC: 1156 AN: 3310

European-Non Finnish (NFE) AF: 0.433 AC: 422758 AN: 977054

Other (OTH) AF: 0.414 AC: 20016 AN: 48404

GnomAD4 genome AF: 0.366 AC: 55043 AN: 150276 Hom.: 10586 Cov.: 31 AF XY: 0.369 AC XY: 27065 AN XY: 73432

African (AFR) AF: 0.236 AC: 9727 AN: 41282

American (AMR) AF: 0.379 AC: 5730 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1357 AN: 3458

East Asian (EAS) AF: 0.348 AC: 1770 AN: 5088

South Asian (SAS) AF: 0.446 AC: 2147 AN: 4816

European-Finnish (FIN) AF: 0.452 AC: 4479 AN: 9906

Middle Eastern (MID) AF: 0.286 AC: 83 AN: 290

European-Non Finnish (NFE) AF: 0.426 AC: 28695 AN: 67336

Other (OTH) AF: 0.367 AC: 767 AN: 2090

Alfa AF: 0.266 Hom.: 693

Bravo AF: 0.355

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)
-	-	2	not provided (2)
-	-	1	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13051066; hg19: chr21-36164405;