21-34788755-T-C

Position:

• chr21-34788755-T-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: The NM_001754.4:c.*3380A>G variant in the 3' UTR has an MAF of 0.08 (8%, 3561/42024 alleles) in the African subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 131 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/CA10650413/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.029 (151 hom., cov: 32)
  • Exomes 𝑓: 0.010 (28 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.573

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 -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.*3380A>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	ENST00000675419.1	c.*3380A>G		3_prime_UTR_variant	9/9		NM_001754.5	ENSP00000501943	A1
RUNX1	ENST00000300305.7	c.*3380A>G		3_prime_UTR_variant	8/8	1		ENSP00000300305	A1
RUNX1	ENST00000344691.8	c.*3380A>G		3_prime_UTR_variant	6/6	1		ENSP00000340690	P4
RUNX1	ENST00000437180.5	c.*3380A>G		3_prime_UTR_variant	9/9	5		ENSP00000409227	A1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4358 AN: 152192 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.0855

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0263

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0104 AC: 847 AN: 81260 Hom.: 28 Cov.: 0 AF XY: 0.00957 AC XY: 358 AN XY: 37408

Gnomad4 AFR exome AF: 0.0914

Gnomad4 AMR exome AF: 0.0452

Gnomad4 ASJ exome AF: 0.000586

Gnomad4 EAS exome AF: 0.0242

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000400

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0287 AC: 4368 AN: 152310 Hom.: 151 Cov.: 32 AF XY: 0.0285 AC XY: 2122 AN XY: 74470

Gnomad4 AFR AF: 0.0855

Gnomad4 AMR AF: 0.0362

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0262

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0128 Hom.: 7

Bravo AF: 0.0336

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:2

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. -
Benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Jan 13, 2020	The NM_001754.4:c.*3380A>G variant in the 3' UTR has an MAF of 0.08 (8%, 3561/42024 alleles) in the African subpopulation of the gnomAD v3 cohort and is =/> 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 131 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.53

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: rs79122814; hg19: chr21-36161052;