chr21-34787995-G-A

Position:

• chr21-34787995-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.*4140C>T variant in the 3' UTR has an MAF of 0.005246 (0.5%, 16/3050 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual 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/CA10644610/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (2 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 0.0770

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.*4140C>T		3_prime_UTR_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.*4140C>T		3_prime_UTR_variant	9/9		NM_001754.5	A1
RUNX1	ENST00000300305.7	c.*4140C>T		3_prime_UTR_variant	8/8	1		A1
RUNX1	ENST00000344691.8	c.*4140C>T		3_prime_UTR_variant	6/6	1		P4
RUNX1	ENST00000437180.5	c.*4140C>T		3_prime_UTR_variant	9/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00392

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00622

GnomAD4 exome AF: 0.00497 AC: 402 AN: 80964 Hom.: 2 Cov.: 0 AF XY: 0.00534 AC XY: 199 AN XY: 37240

Gnomad4 AFR exome AF: 0.00360

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.0000878

Gnomad4 SAS exome AF: 0.00570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00544

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00337 AC: 514 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74500

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.00361

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RUNX1: BS1, BS2 -

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.*4140C>T variant in the 3' UTR has an MAF of 0.005246 (0.5%, 16/3050 alleles) in the South Asian subpopulation of the gnomAD v3 cohort and is >= 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual 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 12, 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	-0.84
CADD	Benign	4.8
DANN	Benign	0.73

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: rs141693054; hg19: chr21-36160292;