rs59802347

chr21-34799341-G-Achr21-34799341-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001754.5(RUNX1):c.927C>T(p.Gly309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,208 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (9 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 1.01

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 21-34799341-G-A is Benign according to our data. Variant chr21-34799341-G-A is described in ClinVar as [Benign]. Clinvar id is 239057.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1565/152326) while in subpopulation AFR AF= 0.036 (1495/41572). AF 95% confidence interval is 0.0344. There are 24 homozygotes in gnomad4. There are 751 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1561 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.927C>T	p.Gly309=	synonymous_variant	8/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.927C>T	p.Gly309=	synonymous_variant	8/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1561 AN: 152208 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00282 AC: 709 AN: 251490 Hom.: 10 AF XY: 0.00205 AC XY: 278 AN XY: 135922

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00103 AC: 1499 AN: 1461882 Hom.: 9 Cov.: 31 AF XY: 0.000862 AC XY: 627 AN XY: 727244

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0103 AC: 1565 AN: 152326 Hom.: 24 Cov.: 32 AF XY: 0.0101 AC XY: 751 AN XY: 74484

Gnomad4 AFR AF: 0.0360

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00624 Hom.: 9

Bravo AF: 0.0121

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

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, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

RUNX1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2021

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jan 12, 2021

This synonymous variant is present in gnomAD (v2 and v3) at an allele frequency >0.15% with at least 5 alleles in any general continental population (BA1); in addition, the variant was found in homozygosity in the population database (BP2). Although the variant is predicted by SSF and MES to create a putative cryptic donor splice site at c.925 (insignificant prediction by SpliceAI), evolutionary conservation prediction algorithms predict the site as being weakly conserved (PhyloP score: 1.25 > 0.1 [-14.1;6.4]), and the variant is not the reference nucleotide in one primate and/or three mammal species, SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10%. In summary, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP2. -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	10
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs59802347; hg19: chr21-36171638;