chr21-34788103-A-G

Position:

• chr21-34788103-A-G

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.*4032T>C variant reported at an MAF of 0.096 (9%, 835/8702 alleles) in the African population in gnomAD cohort is ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 25 individuals in gnomAD (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/CA10653545/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.027 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (22 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.561

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.*4032T>C		3_prime_UTR_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.*4032T>C		3_prime_UTR_variant	9/9		NM_001754.5	A1
RUNX1	ENST00000300305.7	c.*4032T>C		3_prime_UTR_variant	8/8	1		A1
RUNX1	ENST00000344691.8	c.*4032T>C		3_prime_UTR_variant	6/6	1		P4
RUNX1	ENST00000437180.5	c.*4032T>C		3_prime_UTR_variant	9/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4104 AN: 152136 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.00628 AC: 509 AN: 80996 Hom.: 22 Cov.: 0 AF XY: 0.00580 AC XY: 216 AN XY: 37234

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00998

Gnomad4 ASJ exome AF: 0.000585

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0271 AC: 4128 AN: 152254 Hom.: 174 Cov.: 32 AF XY: 0.0255 AC XY: 1895 AN XY: 74456

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0123 Hom.: 8

Bravo AF: 0.0308

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Jan 13, 2020	The NM_001754.4:c.*4032T>C variant reported at an MAF of 0.096 (9%, 835/8702 alleles) in the African population in gnomAD cohort is =/> 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 25 individuals in gnomAD (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. -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.2
DANN	Benign	0.67

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: rs78335539; hg19: chr21-36160400;