chr21-34787885-G-A

Position:

• chr21-34787885-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.*4250C>T variant in the 3' UTR has an MAF of 0.002009 (0.2%, 31/15430 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 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/CA10644601/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (0 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 4.54

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.*4250C>T		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.*4250C>T		3_prime_UTR_variant	9/9		NM_001754.5	ENSP00000501943	A1
RUNX1	ENST00000300305.7	c.*4250C>T		3_prime_UTR_variant	8/8	1		ENSP00000300305	A1
RUNX1	ENST00000344691.8	c.*4250C>T		3_prime_UTR_variant	6/6	1		ENSP00000340690	P4
RUNX1	ENST00000437180.5	c.*4250C>T		3_prime_UTR_variant	9/9	5		ENSP00000409227	A1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000951 AC: 77 AN: 80970 Hom.: 0 Cov.: 0 AF XY: 0.00105 AC XY: 39 AN XY: 37216

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.000444

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74498

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00461

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.000691

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.*4250C>T variant in the 3' UTR has an MAF of 0.002009 (0.2%, 31/15430 alleles) in the non-Finnish European subpopulation of the gnomAD v2.1.1 cohort and is >= 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 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	-0.26
CADD	Benign	14
DANN	Benign	0.83

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: rs186103543; hg19: chr21-36160182;