rs1172332120

Positions:

• chr21-34792321-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP7 BS1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.1257G>A (p.Val419=) is a synonymous variant which meets criteria for likely benign classification. The MAF is 0.0001369 (0.01369%, 7/51146 alleles) in the Admixed American subpopulation of the gnomAD v4.1.0 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). It has a SpliceAI score ≤ 0.20 (Donor gain Δ score 0.01) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.370)) (BP7). 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, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512341177/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: 0.429

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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	c.1257G>A	p.Val419Val	synonymous_variant	9/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.1257G>A	p.Val419Val	synonymous_variant	9/9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000323 AC: 5 AN: 154920 Hom.: 0 AF XY: 0.0000241 AC XY: 2 AN XY: 83104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000200

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1400146 Hom.: 0 Cov.: 36 AF XY: 0.00000434 AC XY: 3 AN XY: 691550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 28, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

This alteration is classified as likely 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. -

RUNX1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jan 15, 2025

NM_001754.5(RUNX1):c.1257G>A (p.Val419=) is a synonymous variant which meets criteria for likely benign classification. The MAF is 0.0001369 (0.01369%, 7/51146 alleles) in the Admixed American subpopulation of the gnomAD v4.1.0 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). It has a SpliceAI score ≤ 0.20 (Donor gain Δ score 0.01) (BP4), and evolutionary conservation algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.370)) (BP7). 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, BP7. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1172332120; hg19: chr21-36164618;