rs145230602

chr21-34834561-G-Achr21-34834561-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001754.5(RUNX1):c.654C>T(p.Ser218=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000425 in 1,612,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:7
• Conservation: PhyloP100: 4.60

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 21-34834561-G-A is Benign according to our data. Variant chr21-34834561-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239052.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000407 (595/1460544) while in subpopulation MID AF= 0.00325 (16/4930). AF 95% confidence interval is 0.00204. There are 0 homozygotes in gnomad4_exome. There are 297 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.654C>T	p.Ser218=	synonymous_variant	7/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.654C>T	p.Ser218=	synonymous_variant	7/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.000599 AC: 91 AN: 151960 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000518 AC: 130 AN: 250760 Hom.: 0 AF XY: 0.000531 AC XY: 72 AN XY: 135540

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000407 AC: 595 AN: 1460544 Hom.: 0 Cov.: 33 AF XY: 0.000409 AC XY: 297 AN XY: 726578

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.000979

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152078 Hom.: 0 Cov.: 31 AF XY: 0.000619 AC XY: 46 AN XY: 74318

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000952 Hom.: 0

Bravo AF: 0.000771

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:3

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	- -
Likely benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Aug 02, 2019	The MAF of the synonymous variant, NM_001754.4:c.654C>T (p.Ser218=), is 0.00105 (0.1%, 36/34418 alleles) in the Latino subpopulation of the gnomAD cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This synonymous variant is predicted by SSF and MES to lead to 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, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	This variant is associated with the following publications: (PMID: 27106701) -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 05, 2018	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 28, 2020

- -

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	-0.49
Cadd	Benign	11
Dann	Benign	0.72
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: rs145230602; hg19: chr21-36206858;