rs76558016

chr21-34887011-C-Tchr21-34887011-C-G

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.183G>A(p.Pro61=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000753 in 1,602,878 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (9 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 2.88

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=-0.24).
• BP6: Variant 21-34887011-C-T is Benign according to our data. Variant chr21-34887011-C-T is described in ClinVar as [Benign]. Clinvar id is 212088.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=2.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00413 (629/152328) while in subpopulation AFR AF= 0.0145 (602/41564). AF 95% confidence interval is 0.0135. There are 10 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 629 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.183G>A	p.Pro61=	synonymous_variant	4/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.183G>A	p.Pro61=	synonymous_variant	4/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 629 AN: 152214 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00105 AC: 242 AN: 230660 Hom.: 2 AF XY: 0.000850 AC XY: 108 AN XY: 127068

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000590

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: 0.0000192

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000398 AC: 578 AN: 1450550 Hom.: 9 Cov.: 35 AF XY: 0.000338 AC XY: 244 AN XY: 721568

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000811

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.000649

GnomAD4 genome AF: 0.00413 AC: 629 AN: 152328 Hom.: 10 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74488

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000525 Hom.: 0

Bravo AF: 0.00470

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 01, 2016	- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Aug 08, 2020

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 evolutionary conservation prediction algorithms predict the site as being moderately conserved (PhyloP score: 3.03 > 0.1 [-14.1;6.4]) and the variant is not the reference nucleotide in one primate and/or three mammal species, it is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (BP4). 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, BP2, and BP4. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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	-0.24
Cadd	Benign	14
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs76558016; hg19: chr21-36259308;