chr21-34788516-T-C

Position:

• chr21-34788516-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 c.*3619A>G variant in the 3' UTR has an MAF of 0.02813 (2.8%, 384/13650 alleles) in the Latino subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 11 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/CA10652906/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0079 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (10 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 1.79

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.*3619A>G		3_prime_UTR_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.*3619A>G		3_prime_UTR_variant	9/9		NM_001754.5	A1
RUNX1	ENST00000300305.7	c.*3619A>G		3_prime_UTR_variant	8/8	1		A1
RUNX1	ENST00000344691.8	c.*3619A>G		3_prime_UTR_variant	6/6	1		P4
RUNX1	ENST00000437180.5	c.*3619A>G		3_prime_UTR_variant	9/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1200 AN: 152118 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0252

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00563 AC: 455 AN: 80876 Hom.: 10 Cov.: 0 AF XY: 0.00508 AC XY: 189 AN XY: 37236

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00788 AC: 1199 AN: 152236 Hom.: 14 Cov.: 32 AF XY: 0.00883 AC XY: 657 AN XY: 74426

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0251

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00537 Hom.: 1

Bravo AF: 0.0100

Asia WGS AF: 0.0140 AC: 50 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

May 13, 2020

The c.*3619A>G variant in the 3' UTR has an MAF of 0.02813 (2.8%, 384/13650 alleles) in the Latino subpopulation of the gnomAD v3 cohort and is >= 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 11 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. -

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	-0.23
CADD	Benign	13
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs139372063; hg19: chr21-36160813;