rs752586117

chr21-34859535-C-Achr21-34859535-C-Tchr21-34859535-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001754.5(RUNX1):c.552G>T(p.Pro184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,110 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 Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P184P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -7.01

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]

RUNX1-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 21-34859535-C-A is Benign according to our data. Variant chr21-34859535-C-A is described in ClinVar as [Benign]. Clinvar id is 463997.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-7.01 with no splicing effect.
• BS2: High AC in GnomAdExome at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.552G>T	p.Pro184=	synonymous_variant	6/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.552G>T	p.Pro184=	synonymous_variant	6/9		NM_001754.5	A1
RUNX1-AS1	ENST00000651798.1	n.661+22589C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251492 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00169

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461868 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2017

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Aug 24, 2020

The c.552G>T variant predicts a synonymous change, Pro184= and has an MAF of 0.001654 (0.17%, 33/19954 alleles) in the East Asian subpopulation of the gnomAD v2.1.1 cohort and is ≥ 0.0015 (0.15%) (BA1). This synonymous variant 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 addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score -8.975 < 0.1) (BP7). 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, BP4, BP7. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.49
Dann	Benign	0.87
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: rs752586117; hg19: chr21-36231832; COSMIC: COSV55891073; COSMIC: COSV55891073;