rs117776183

Positions:

• chr21-35048819-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BP2 BA1 BP7

This summary comes from the ClinGen Evidence Repository: This intronic variant has a MAF of 0.008015 (0.8015%, 545/67996 alleles) in the European (non-Finnish) subpopulation of gnomAD v3.1.2 cohort is ≥0.0015 (0.15%) (BA1). It is detected in a homozygous state in 9 individuals within the European (non-Finnish) population in gnomAD v2.1.1 (NB: MAF for this allele within the European (non-Finnish) population of gnomAD v2.1.1 is 0.008492 (0.8492%, 1097/129174 alleles) (BP2). It has a SpliceAI Δ score of ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.666583 is <2.0). The variant is the reference nucleotide in at least 3 mammalian species. It is not the reference nucleotide in any primate (BP7). 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, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014719/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (54 hom.)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.739

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.58+23A>G		intron_variant		ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.58+23A>G		intron_variant			NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 702 AN: 152072 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00802

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00438 AC: 1102 AN: 251454 Hom.: 11 AF XY: 0.00413 AC XY: 561 AN XY: 135908

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00867

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00705 AC: 10220 AN: 1450342 Hom.: 54 Cov.: 29 AF XY: 0.00681 AC XY: 4918 AN XY: 722284

Gnomad4 AFR exome AF: 0.000932

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.000691

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00259

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152190 Hom.: 3 Cov.: 31 AF XY: 0.00399 AC XY: 297 AN XY: 74406

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00802

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00454 Hom.: 0

Bravo AF: 0.00450

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2018

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jun 24, 2024

This intronic variant has a MAF of 0.008015 (0.8015%, 545/67996 alleles) in the European (non-Finnish) subpopulation of gnomAD v3.1.2 cohort is ≥0.0015 (0.15%) (BA1). It is detected in a homozygous state in 9 individuals within the European (non-Finnish) population in gnomAD v2.1.1 (NB: MAF for this allele within the European (non-Finnish) population of gnomAD v2.1.1 is 0.008492 (0.8492%, 1097/129174 alleles) (BP2). It has a SpliceAI Δ score of ≤0.20 (0.00) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score 0.666583 is <2.0). The variant is the reference nucleotide in at least 3 mammalian species. It is not the reference nucleotide in any primate (BP7). 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, BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.76

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: rs117776183; hg19: chr21-36421116;