rs377681816

Variant names:

• chr21-34880539-T-C
• rs377681816
• NM_001754.5:c.508+18A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-34880539-T-C
• chr21-34880539-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7 BS1 BP4

This summary comes from the ClinGen Evidence Repository: MAF of 0.00018 (0.018%, 23/129128 alleles) in the European (Non-Finnish) subpopulation of the gnomAD cohort is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This intronic variant has a SpliceAI score ≤ 0.20 (0.02) (BP4). Evolutionary conservation prediction algorithms predict the site as not being conserved, as it is the reference nucleotide in chimps in UCSC GRCh38 (BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014497/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: -1.47
• Publications: 0 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-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.508+18A>G		intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.427+18A>G		intron	N/A	NP_001001890.1
	RUNX1	NM_001122607.2		c.427+18A>G		intron	N/A	NP_001116079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.508+18A>G		intron	N/A	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.508+18A>G		intron	N/A	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.427+18A>G		intron	N/A	ENSP00000340690.4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251370 AF XY: 0.0000662

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000337 AC: 492 AN: 1461454 Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 218 AN XY: 727066

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000426 AC: 474 AN: 1111660

Other (OTH) AF: 0.000149 AC: 9 AN: 60372

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74370

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000136

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.8
DANN	Benign	0.74
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs377681816; hg19: chr21-36252836;