rs147889692

chr21-34887050-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001754.5(RUNX1):c.144C>T(p.Ser48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,600,640 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (31 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 1.14

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 21-34887050-G-A is Benign according to our data. Variant chr21-34887050-G-A is described in ClinVar as [Benign]. Clinvar id is 239043.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS2: High AC in GnomAd at 495 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.144C>T	p.Ser48=	synonymous_variant	4/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.144C>T	p.Ser48=	synonymous_variant	4/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 495 AN: 152216 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00286 AC: 664 AN: 232018 Hom.: 4 AF XY: 0.00294 AC XY: 377 AN XY: 128248

Gnomad AFR exome AF: 0.000143

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.00191 AC: 2768 AN: 1448314 Hom.: 31 Cov.: 35 AF XY: 0.00184 AC XY: 1330 AN XY: 721012

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152326 Hom.: 5 Cov.: 32 AF XY: 0.00469 AC XY: 349 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0349

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.000756

EpiCase AF: 0.00153

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	RUNX1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 31, 2018

- -

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). The 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, and evolutionary conservation prediction algorithms predict the site as being not highly conserved (PhyloP score: 1.01 [-14.1;6.4]) (BP4; BP7). 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, BP4 and BP7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	14
Dann	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147889692; hg19: chr21-36259347;