rs535532916

Positions:

• chr21-34792091-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.*44C>G is a 3' UTR variant. MAF of 0.01 (1.31%, 885/67420 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 4 homozygotes in gnomAD v3.1.2 (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/CA10014163/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0085 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (110 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.209

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.*44C>G		3_prime_UTR_variant	9/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419	c.*44C>G		3_prime_UTR_variant	9/9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes AF: 0.00852 AC: 1281 AN: 150344 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00240

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00624

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00725

GnomAD3 exomes AF: 0.0109 AC: 59 AN: 5428 Hom.: 0 AF XY: 0.0112 AC XY: 39 AN XY: 3478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.0348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00791

Gnomad FIN exome AF: 0.00987

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00658

GnomAD4 exome AF: 0.0124 AC: 13700 AN: 1104612 Hom.: 110 Cov.: 17 AF XY: 0.0123 AC XY: 6571 AN XY: 536204

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.0340

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00529

Gnomad4 FIN exome AF: 0.00665

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00852 AC: 1282 AN: 150452 Hom.: 4 Cov.: 32 AF XY: 0.00834 AC XY: 613 AN XY: 73504

Gnomad4 AFR AF: 0.00239

Gnomad4 AMR AF: 0.00623

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.00717

Alfa AF: 0.0106 Hom.: 2

Bravo AF: 0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jun 30, 2022

NM_001754.5(RUNX1):c.*44C>G is a 3' UTR variant. MAF of 0.01 (1.31%, 885/67420 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 4 homozygotes in gnomAD v3.1.2 (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 -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.72
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

Publications

LitVar

Other links and lift over

dbSNP: rs535532916; hg19: chr21-36164388;