rs61750222

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP2BP4BA1BP7

This summary comes from the ClinGen Evidence Repository: The MAF for the synonymous variant, NM_001754.4:c.1389C>G (p.Pro463=) is 0.1206 (12%, 1976/16382 alleles) in the African subpopulation of the gnomAD cohort, which is ≥ 0.0015 (0.15%) (BA1). This 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). This synonymous variant is predicted by evolutionary conservation prediction algorithms that the site is not conserved (PhyloP score -0.503315 <0.1) (BP7). This variant is detected in a homozygous state in 202 individuals in a gnomAD (BP2). 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, BP2, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014178/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.045 ( 356 hom., cov: 31)

Exomes 𝑓: 0.016 ( 552 hom. )

Consequence

RUNX1
NM_001754.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -0.485

Variant links:

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 links:

RUNX1 (HGNC:):

RUNX1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.1389C>G	p.Pro463Pro	synonymous_variant	9/9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.1389C>G	p.Pro463Pro	synonymous_variant	9/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0453

AC:

6873

AN:

151862

Hom.:

349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0457

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.000853

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00925

Gnomad OTH

AF:

0.0378

GnomAD3 exomes

AF:

0.0311

AC:

4309

AN:

138592

Hom.:

138

AF XY:

0.0283

AC XY:

2134

AN XY:

75510

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0552

Gnomad ASJ exome

AF:

0.0616

Gnomad EAS exome

AF:

0.0216

Gnomad SAS exome

AF:

0.0294

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00925

Gnomad OTH exome

AF:

0.0255

GnomAD4 exome

AF:

0.0157

AC:

21791

AN:

1384492

Hom.:

552

Cov.:

AF XY:

0.0156

AC XY:

10686

AN XY:

683826

show subpopulations

Gnomad4 AFR exome

AF:

0.128

Gnomad4 AMR exome

AF:

0.0537

Gnomad4 ASJ exome

AF:

0.0606

Gnomad4 EAS exome

AF:

0.0227

Gnomad4 SAS exome

AF:

0.0292

Gnomad4 FIN exome

AF:

0.00203

Gnomad4 NFE exome

AF:

0.00891

Gnomad4 OTH exome

AF:

0.0233

GnomAD4 genome

AF:

0.0454

AC:

6906

AN:

151978

Hom.:

356

Cov.:

AF XY:

0.0444

AC XY:

3301

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.0455

Gnomad4 ASJ

AF:

0.0616

Gnomad4 EAS

AF:

0.0249

Gnomad4 SAS

AF:

0.0245

Gnomad4 FIN

AF:

0.000853

Gnomad4 NFE

AF:

0.00925

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0162

Hom.:

Bravo

AF:

0.0519

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2021	- -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Aug 02, 2019	The MAF for the synonymous variant, NM_001754.4:c.1389C>G (p.Pro463=) is 0.1206 (12%, 1976/16382 alleles) in the African subpopulation of the gnomAD cohort, which is >/= 0.0015 (0.15%) (BA1). This 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). This synonymous variant is predicted by evolutionary conservation prediction algorithms that the site is not conserved (PhyloP score -0.503315 <0.1) (BP7). This variant is detected in a homozygous state in 202 individuals in a gnomAD (BP2). 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, BP2, BP4, BP7. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

-0.70

CADD

Benign

6.2

DANN

Benign

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over